U.S. patent number 10,626,104 [Application Number 16/289,278] was granted by the patent office on 2020-04-21 for inhibitors of lysine specific demethylase-1.
This patent grant is currently assigned to Celgene Quanticel Research, Inc.. The grantee listed for this patent is CELGENE QUANTICEL RESEARCH, INC.. Invention is credited to Young K. Chen, Toufike Kanouni, Zhe Nie, Jeffrey Alan Stafford, James Marvin Veal.
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United States Patent |
10,626,104 |
Chen , et al. |
April 21, 2020 |
Inhibitors of lysine specific demethylase-1
Abstract
The present invention relates generally to compositions and
methods for treating cancer and neoplastic disease. Provided herein
are substituted heterocyclic derivative compounds and
pharmaceutical compositions comprising said compounds. The subject
compounds and compositions are useful for inhibition of lysine
specific demethylase-1. Furthermore, the subject compounds and
compositions are useful for the treatment of cancer, such as
prostate cancer, breast cancer, bladder cancer, lung cancer and/or
melanoma and the like.
Inventors: |
Chen; Young K. (San Marcos,
CA), Kanouni; Toufike (La Jolla, CA), Nie; Zhe (San
Diego, CA), Stafford; Jeffrey Alan (San Diego, CA), Veal;
James Marvin (Apex, NC) |
Applicant: |
Name |
City |
State |
Country |
Type |
CELGENE QUANTICEL RESEARCH, INC. |
San Diego |
CA |
US |
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Assignee: |
Celgene Quanticel Research,
Inc. (San Diego, CA)
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Family
ID: |
55019933 |
Appl.
No.: |
16/289,278 |
Filed: |
February 28, 2019 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20190194162 A1 |
Jun 27, 2019 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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15323384 |
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PCT/US2015/038661 |
Jun 30, 2015 |
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62020758 |
Jul 3, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D
403/12 (20130101); A61P 35/00 (20180101); C07D
403/06 (20130101); C07D 403/14 (20130101); C07D
401/06 (20130101); C07D 401/12 (20130101); C07D
403/04 (20130101); C07D 401/14 (20130101); C07D
487/10 (20130101) |
Current International
Class: |
C07D
401/06 (20060101); C07D 487/10 (20060101); A61P
35/00 (20060101); C07D 403/04 (20060101); C07D
403/06 (20060101); C07D 403/14 (20060101); C07D
403/12 (20060101); C07D 401/14 (20060101); C07D
401/12 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO-03057699 |
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Jul 2003 |
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JP |
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2014/151945 |
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Sep 2014 |
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WO |
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Other References
Extended European Search Report dated Jan. 26, 2018 in related
European Application No. 15815609.1, filed Jun. 30, 2015. cited by
applicant .
Written Opinion and Search Report dated Oct. 24, 2017 in related
Singapore Application No. 11201700007Y, filed Jun. 30, 2015. cited
by applicant .
International Preliminary Report on Patentability, dated Jan. 12,
2017, in related international Patent Application No.
PCT/US2015/038661, filed Jun. 30, 2015. cited by applicant .
International Search Report and Written Opinion, dated Sep. 30,
2015, in related International Patent Application No.
PCT/US2015/038661, filed Jun. 30, 2015. cited by applicant .
Notice of Allowance/Allowability dated Nov. 28, 2018 in U.S. Appl.
No. 15/323,384, filed Dec. 30, 2016. cited by applicant .
Official Action issued in co-pending U.S. Appl. No. 16/288,085,
dated Aug. 6, 2019. cited by applicant .
Notice of Allowance issued in co-pending U.S. Appl. No. 16/288,085,
dated Nov. 19, 2019. cited by applicant.
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Primary Examiner: Davis; Zinna Northington
Attorney, Agent or Firm: Foley & Lardner LLP
Parent Case Text
CROSS-REFERENCE
This application is a divisional application of U.S. patent
application Ser. No. 15/323,384, filed Dec. 30, 2016, now U.S. Pat.
No. 10,414,750, which is a the U.S. National Stage of International
Patent Application No. PCT/US2015/038661, filed Jun. 30, 2015,
which claims the benefit of U.S. Provisional Application
62/020,758, filed Jul. 3, 2014, the contents of which are hereby
incorporated by reference in their entireties.
Claims
We claim:
1. A method of treating prostate cancer in a patient in need
thereof, comprising administering to the patient a therapeutic
effective amount of a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, ##STR00482## wherein, A
is C; B is N; and D is C--R.sup.3; R.sup.3 is hydrogen; W.sup.1 and
W.sup.2 are C--H; X is chosen from aryl optionally substituted with
halogen, alkyl, or alkoxy; or heteroaryl optionally substituted
with halogen, alkyl, alkoxy, or cycloalkyl; Y is chosen from
hydrogen, halogen, alkyl optionally substituted with --OH, alkoxy,
or carbonyl; and Z is N-heterocyclyl optionally substituted with
--NH.sub.2, amine, or alkyl.
2. The method of claim 1, wherein X is aryl optionally substituted
with halogen, alkyl, or alkoxy.
3. The method of claim 2, wherein the aryl is phenyl.
4. The method of claim 1, wherein X is heteroaryl optionally
substituted with halogen, alkyl, alkoxy, or cycloalkyl.
5. The method of claim 4, wherein the heteroaryl is chosen from
pyridinyl, pyrimidinyl, pyrazinyl, pyrazolyl, indazolyl,
azaindazolyl, isoindazolyl, indolyl, or azaindolyl.
6. The method of claim 1, wherein Z is N-heterocyclyl optionally
substituted with --NH.sub.2, amine, or alkyl and the N-heterocyclyl
is a 4-, 5-, 6-, or 7-membered N-heterocyclyl.
7. The method of claim 6, wherein the N-heterocyclyl is a
6-membered N-heterocyclyl.
8. The method of claim 7, wherein the N-heterocyclyl is
piperidine.
9. The method of claim 8, wherein the piperidine is
3-aminopiperidine.
10. The method of claim 6, wherein the N-heterocyclyl is a
5-membered N-heterocyclyl.
11. The method of claim 10, wherein the N-heterocyclyl is
pyrrolidine.
12. The method of claim 11, wherein the pyrrolidine is
3-aminopyrrolidine.
13. The method of claim 1, wherein Y is hydrogen.
14. The method of claim 1, wherein Y is halogen.
15. The method of claim 1, wherein Y is alkyl optionally
substituted with --OH, alkoxy, or carbonyl.
16. The method of claim 15, wherein the alkyl is C.sub.1-C.sub.3
alkyl.
17. The method of claim 15, wherein the alkyl is C.sub.1 alkyl.
Description
BACKGROUND
A need exists in the art for an effective treatment of cancer and
neoplastic disease.
BRIEF SUMMARY OF THE INVENTION
Provided herein are substituted heterocyclic derivative compounds
and pharmaceutical compositions comprising said compounds. The
subject compounds and compositions are useful for the inhibition of
the enzyme lysine specific demethylase-1 (LSD-1). Furthermore, the
subject compounds and compositions are useful for the treatment of
cancer, such as prostate cancer, breast cancer, bladder cancer,
lung cancer and/or melanoma and the like. The substituted
heterocyclic derivative compounds described herein are based upon a
central heterocyclic ring system, such as pyrrole or imidazole, or
the like. Said central heterocyclic ring system is further
substituted with a 4-cyanophenyl group and a substituted amide
group.
One embodiment provides a compound having the structure of Formula
(I), or a pharmaceutically acceptable salt thereof,
##STR00001##
wherein, A is C; B is N; and D is C--R.sup.3; or A is N; B is C;
and D is N; each R.sup.3 is independently chosen from hydrogen or
optionally substituted alkyl; W.sup.1 and W.sup.2 are independently
chosen from N, C--H, or C--F; X is chosen from optionally
substituted aryl, optionally substituted heteroaryl, optionally
substituted cycloalkyl, optionally substituted alkyl, optionally
substituted heterocyclyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclylalkyl, optionally substituted
aralkyl, or optionally substituted heteroarylalkyl; Y is chosen
from hydrogen, halogen, optionally substituted alkyl, optionally
substituted cycloalkyl, or optionally substituted cycloalkylalkyl;
and Z is chosen from an optionally substituted N-heterocyclyl,
optionally substituted --N(H)-heterocyclylalkyl, optionally
substituted --N(Me)-heterocyclylalkyl, or --N(R.sup.3).sub.2.
One embodiment provides a pharmaceutical composition comprising a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable excipient.
One embodiment provides a method of regulating gene transcription
in a cell comprising inhibiting lysine-specific demethylase 1
activity by exposing the lysine-specific demethylase 1 enzyme to a
compound of Formula (I).
One embodiment provides a method of treating cancer in a patient in
need thereof, comprising administering to the patient a compound of
Formula (I), or a pharmaceutically acceptable salt thereof.
INCORPORATION BY REFERENCE
All publications, patents, and patent applications mentioned in
this specification are herein incorporated by reference to the same
extent as if each individual publication, patent, or patent
application was specifically and individually indicated to be
incorporated by reference.
DETAILED DESCRIPTION OF THE INVENTION
As used herein and in the appended claims, the singular forms "a,"
"and," and "the" include plural referents unless the context
clearly dictates otherwise. Thus, for example, reference to "an
agent" includes a plurality of such agents, and reference to "the
cell" includes reference to one or more cells (or to a plurality of
cells) and equivalents thereof known to those skilled in the art,
and so forth. When ranges are used herein for physical properties,
such as molecular weight, or chemical properties, such as chemical
formulae, all combinations and subcombinations of ranges and
specific embodiments therein are intended to be included. The term
"about" when referring to a number or a numerical range means that
the number or numerical range referred to is an approximation
within experimental variability (or within statistical experimental
error), and thus the number or numerical range may vary between 1%
and 15% of the stated number or numerical range. The term
"comprising" (and related terms such as "comprise" or "comprises"
or "having" or "including") is not intended to exclude that in
other certain embodiments, for example, an embodiment of any
composition of matter, composition, method, or process, or the
like, described herein, may "consist of" or "consist essentially
of" the described features.
Definitions
As used in the specification and appended claims, unless specified
to the contrary, the following terms have the meaning indicated
below.
"Amino" refers to the --NH.sub.2 radical.
"Cyano" refers to the --CN radical.
"Nitro" refers to the --NO.sub.2 radical.
"Oxa" refers to the --O-- radical.
"Oxo" refers to the .dbd.O radical.
"Thioxo" refers to the .dbd.S radical.
"Imino" refers to the .dbd.N--H radical.
"Oximo" refers to the .dbd.N--OH radical.
"Hydrazino" refers to the .dbd.N--NH.sub.2 radical.
"Alkyl" refers to a straight or branched hydrocarbon chain radical
consisting solely of carbon and hydrogen atoms, containing no
unsaturation, having from one to fifteen carbon atoms (e.g.,
C.sub.1-C.sub.15 alkyl). In certain embodiments, an alkyl comprises
one to thirteen carbon atoms (e.g., C.sub.1-C.sub.13 alkyl). In
certain embodiments, an alkyl comprises one to eight carbon atoms
(e.g., C.sub.1-C.sub.8 alkyl). In other embodiments, an alkyl
comprises one to five carbon atoms (e.g., C.sub.1-C.sub.5 alkyl).
In other embodiments, an alkyl comprises one to four carbon atoms
(e.g., C.sub.1-C.sub.4 alkyl). In other embodiments, an alkyl
comprises one to three carbon atoms (e.g., C.sub.1-C.sub.3 alkyl).
In other embodiments, an alkyl comprises one to two carbon atoms
(e.g., C.sub.1-C.sub.2 alkyl). In other embodiments, an alkyl
comprises one carbon atom (e.g., C.sub.1 alkyl). In other
embodiments, an alkyl comprises five to fifteen carbon atoms (e.g.,
C.sub.5-C.sub.15 alkyl). In other embodiments, an alkyl comprises
five to eight carbon atoms (e.g., C.sub.5-C.sub.8 alkyl). In other
embodiments, an alkyl comprises two to five carbon atoms (e.g.,
C.sub.2-C.sub.5 alkyl). In other embodiments, an alkyl comprises
three to five carbon atoms (e.g., C.sub.3-C.sub.5 alkyl). In other
embodiments, the alkyl group is selected from methyl, ethyl,
1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl),
1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl),
1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is
attached to the rest of the molecule by a single bond. Unless
stated otherwise specifically in the specification, an alkyl group
is optionally substituted by one or more of the following
substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,
trimethylsilanyl, --OR.sup.a, --SR.sup.a, --OC(O)--R.sup.a,
--N(R.sup.a).sub.2, --C(O)R.sup.a, --C(O)OR.sup.a,
--C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)O R.sup.a, --OC(O)--
N(R.sup.a).sub.2, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2), --S(O).sub.tR.sup.a
(where t is 1 or 2) and --S(O).sub.tN(R.sup.a).sub.2 (where t is 1
or 2) where each R.sup.a is independently hydrogen, alkyl
(optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl),
carbocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), aryl (optionally substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heterocyclylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heteroaryl (optionally substituted with halogen, hydroxy, methoxy,
or trifluoromethyl), or heteroarylalkyl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl).
"Alkoxy" refers to a radical bonded through an oxygen atom of the
formula --O-alkyl, where alkyl is an alkyl chain as defined
above.
"Alkenyl" refers to a straight or branched hydrocarbon chain
radical group consisting solely of carbon and hydrogen atoms,
containing at least one carbon-carbon double bond, and having from
two to twelve carbon atoms. In certain embodiments, an alkenyl
comprises two to eight carbon atoms. In other embodiments, an
alkenyl comprises two to four carbon atoms. The alkenyl is attached
to the rest of the molecule by a single bond, for example, ethenyl
(i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl,
penta-1,4-dienyl, and the like. Unless stated otherwise
specifically in the specification, an alkenyl group is optionally
substituted by one or more of the following substituents: halo,
cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,
--OR.sup.a, --SR.sup.a, --OC(O)--R.sup.a, --N(R.sup.a).sub.2,
--C(O)R.sup.a, --C(O)OR.sup.a, --C(O)N(R.sup.a).sub.2,
--N(R.sup.a)C(O)OR.sup.a, --OC(O)-- N(R.sup.a).sub.2,
--N(R.sup.a)C(O)R.sup.a, --N(R.sup.a)S(O).sub.tR.sup.a (where t is
1 or 2), --S(O).sub.tOR.sup.a (where t is 1 or 2),
--S(O).sub.tR.sup.a (where t is 1 or 2) and
--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2) where each R.sup.a
is independently hydrogen, alkyl (optionally substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl,
carbocyclyl (optionally substituted with halogen, hydroxy, methoxy,
or trifluoromethyl), carbocyclylalkyl (optionally substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
aralkyl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), heterocyclyl (optionally substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl
(optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), heteroaryl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl
(optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl).
"Alkynyl" refers to a straight or branched hydrocarbon chain
radical group consisting solely of carbon and hydrogen atoms,
containing at least one carbon-carbon triple bond, having from two
to twelve carbon atoms. In certain embodiments, an alkynyl
comprises two to eight carbon atoms. In other embodiments, an
alkynyl comprises two to six carbon atoms. In other embodiments, an
alkynyl comprises two to four carbon atoms. The alkynyl is attached
to the rest of the molecule by a single bond, for example, ethynyl,
propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated
otherwise specifically in the specification, an alkynyl group is
optionally substituted by one or more of the following
substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,
trimethylsilanyl, --ORa, --SRa, --OC(O)--Ra, --N(Ra)2, --C(O)Ra,
--C(O)ORa, --C(O)N(Ra)2, --N(Ra) C(O)OR.sup.a, --OC(O)--
N(R.sup.a).sub.2, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2), --S(O).sub.tR.sup.a
(where t is 1 or 2) and --S(O).sub.tN(R.sup.a).sub.2 (where t is 1
or 2) where each R.sup.a is independently hydrogen, alkyl
(optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl),
carbocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), aryl (optionally substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heterocyclylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heteroaryl (optionally substituted with halogen, hydroxy, methoxy,
or trifluoromethyl), or heteroarylalkyl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl).
"Alkylene" or "alkylene chain" refers to a straight or branched
divalent hydrocarbon chain linking the rest of the molecule to a
radical group, consisting solely of carbon and hydrogen, containing
no unsaturation and having from one to twelve carbon atoms, for
example, methylene, ethylene, propylene, n-butylene, and the like.
The alkylene chain is attached to the rest of the molecule through
a single bond and to the radical group through a single bond. The
points of attachment of the alkylene chain to the rest of the
molecule and to the radical group can be through one carbon in the
alkylene chain or through any two carbons within the chain. In
certain embodiments, an alkylene comprises one to eight carbon
atoms (e.g., C.sub.1-C.sub.8 alkylene). In other embodiments, an
alkylene comprises one to five carbon atoms (e.g., C.sub.1-C.sub.5
alkylene). In other embodiments, an alkylene comprises one to four
carbon atoms (e.g., C.sub.1-C.sub.4 alkylene). In other
embodiments, an alkylene comprises one to three carbon atoms (e.g.,
C.sub.1-C.sub.3 alkylene). In other embodiments, an alkylene
comprises one to two carbon atoms (e.g., C.sub.1-C.sub.2 alkylene).
In other embodiments, an alkylene comprises one carbon atom (e.g.,
C.sub.1 alkylene). In other embodiments, an alkylene comprises five
to eight carbon atoms (e.g., C.sub.5-C.sub.8 alkylene). In other
embodiments, an alkylene comprises two to five carbon atoms (e.g.,
C.sub.2-C.sub.5 alkylene). In other embodiments, an alkylene
comprises three to five carbon atoms (e.g., C.sub.3-C.sub.5
alkylene). Unless stated otherwise specifically in the
specification, an alkylene chain is optionally substituted by one
or more of the following substituents: halo, cyano, nitro, oxo,
thioxo, imino, oximo, trimethylsilanyl, --OR.sup.a, --SR.sup.a,
--OC(O)--R.sup.a, --N(R.sup.a).sub.2, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)O R.sup.a,
--OC(O)-- N(R.sup.a).sub.2, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2), --S(O).sub.tR.sup.a
(where t is 1 or 2) and --S(O).sub.tN(R.sup.a).sub.2 (where t is 1
or 2) where each R.sup.a is independently hydrogen, alkyl
(optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl),
carbocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), aryl (optionally substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heterocyclylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heteroaryl (optionally substituted with halogen, hydroxy, methoxy,
or trifluoromethyl), or heteroarylalkyl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl).
"Alkynylene" or "alkynylene chain" refers to a straight or branched
divalent hydrocarbon chain linking the rest of the molecule to a
radical group, consisting solely of carbon and hydrogen, containing
at least one carbon-carbon triple bond, and having from two to
twelve carbon atoms. The alkynylene chain is attached to the rest
of the molecule through a single bond and to the radical group
through a single bond. In certain embodiments, an alkynylene
comprises two to eight carbon atoms (e.g., C.sub.2-C.sub.8
alkynylene). In other embodiments, an alkynylene comprises two to
five carbon atoms (e.g., C.sub.2-C.sub.5 alkynylene). In other
embodiments, an alkynylene comprises two to four carbon atoms
(e.g., C.sub.2-C.sub.4 alkynylene). In other embodiments, an
alkynylene comprises two to three carbon atoms (e.g.,
C.sub.2-C.sub.3 alkynylene). In other embodiments, an alkynylene
comprises two carbon atom (e.g., C.sub.2 alkylene). In other
embodiments, an alkynylene comprises five to eight carbon atoms
(e.g., C.sub.5-C.sub.8 alkynylene). In other embodiments, an
alkynylene comprises three to five carbon atoms (e.g.,
C.sub.3-C.sub.5 alkynylene). Unless stated otherwise specifically
in the specification, an alkynylene chain is optionally substituted
by one or more of the following substituents: halo, cyano, nitro,
oxo, thioxo, imino, oximo, trimethylsilanyl, --OR.sup.a,
--SR.sup.a, --OC(O)--R.sup.a, --N(R.sup.a).sub.2, --C(O)R.sup.a,
--C(O)OR.sup.a, --C(O)N(R.sup.a).sub.2, --N(R.sup.a)C(O)O R.sup.a,
--OC(O)-- N(R.sup.a).sub.2, --N(R.sup.a)C(O)R.sup.a,
--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--S(O).sub.tOR.sup.a (where t is 1 or 2), --S(O).sub.tR.sup.a
(where t is 1 or 2) and --S(O).sub.tN(R.sup.a).sub.2 (where t is 1
or 2) where each R.sup.a is independently hydrogen, alkyl
(optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl),
carbocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), aryl (optionally substituted with
halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heterocyclylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heteroaryl (optionally substituted with halogen, hydroxy, methoxy,
or trifluoromethyl), or heteroarylalkyl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl).
"Aryl" refers to a radical derived from an aromatic monocyclic or
multicyclic hydrocarbon ring system by removing a hydrogen atom
from a ring carbon atom. The aromatic monocyclic or multicyclic
hydrocarbon ring system contains only hydrogen and carbon from five
to eighteen carbon atoms, where at least one of the rings in the
ring system is fully unsaturated, i.e., it contains a cyclic,
delocalized (4n+2) .pi.-electron system in accordance with the
Huckel theory. The ring system from which aryl groups are derived
include, but are not limited to, groups such as benzene, fluorene,
indane, indene, tetralin and naphthalene. Unless stated otherwise
specifically in the specification, the term "aryl" or the prefix
"ar-" (such as in "aralkyl") is meant to include aryl radicals
optionally substituted by one or more substituents independently
selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano,
nitro, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted aralkenyl, optionally substituted aralkynyl,
optionally substituted carbocyclyl, optionally substituted
carbocyclylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.b--OR.sup.a,
--R.sup.b--OC(O)--R.sup.a, --R.sup.b--OC(O)--OR.sup.a,
--R.sup.b--OC(O)--N(R.sup.a).sub.2, --R.sup.b--N(R.sup.a).sub.2,
--R.sup.b--C(O) R.sup.a, --R.sup.b--C(O)OR.sup.a,
--R.sup.b--C(O)N(R.sup.a).sub.2,
--R.sup.b--O--R--C(O)N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a)C(O)OR.sup.a,
--R.sup.b--N(R.sup.a)C(O)R.sup.a,
--R.sup.b--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tOR.sup.a (where t is 1 or 2) and
--R.sup.b--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), where
each R.sup.a is independently hydrogen, alkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
fluoroalkyl, cycloalkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
aryl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), aralkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heteroaryl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl), or
heteroarylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), each R.sup.b is independently a
direct bond or a straight or branched alkylene or alkenylene chain,
and R.sup.c is a straight or branched alkylene or alkenylene chain,
and where each of the above substituents is unsubstituted unless
otherwise indicated.
"Aralkyl" refers to a radical of the formula --R.sup.c-aryl where
R.sup.c is an alkylene chain as defined above, for example,
methylene, ethylene, and the like. The alkylene chain part of the
aralkyl radical is optionally substituted as described above for an
alkylene chain. The aryl part of the aralkyl radical is optionally
substituted as described above for an aryl group.
"Aralkenyl" refers to a radical of the formula --R.sup.d-aryl where
R.sup.d is an alkenylene chain as defined above. The aryl part of
the aralkenyl radical is optionally substituted as described above
for an aryl group. The alkenylene chain part of the aralkenyl
radical is optionally substituted as defined above for an
alkenylene group.
"Aralkynyl" refers to a radical of the formula --R.sup.e-aryl,
where R.sup.e is an alkynylene chain as defined above. The aryl
part of the aralkynyl radical is optionally substituted as
described above for an aryl group. The alkynylene chain part of the
aralkynyl radical is optionally substituted as defined above for an
alkynylene chain.
"Aralkoxy" refers to a radical bonded through an oxygen atom of the
formula --O--R.sup.C-aryl where R.sup.c is an alkylene chain as
defined above, for example, methylene, ethylene, and the like. The
alkylene chain part of the aralkyl radical is optionally
substituted as described above for an alkylene chain. The aryl part
of the aralkyl radical is optionally substituted as described above
for an aryl group.
"Carbocyclyl" refers to a stable non-aromatic monocyclic or
polycyclic hydrocarbon radical consisting solely of carbon and
hydrogen atoms, which includes fused or bridged ring systems,
having from three to fifteen carbon atoms. In certain embodiments,
a carbocyclyl comprises three to ten carbon atoms. In other
embodiments, a carbocyclyl comprises five to seven carbon atoms.
The carbocyclyl is attached to the rest of the molecule by a single
bond. Carbocyclyl may be saturated, (i.e., containing single C--C
bonds only) or unsaturated (i.e., containing one or more double
bonds or triple bonds.) A fully saturated carbocyclyl radical is
also referred to as "cycloalkyl." Examples of monocyclic
cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl
is also referred to as "cycloalkenyl." Examples of monocyclic
cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl,
cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals
include, for example, adamantyl, norbornyl (i.e.,
bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,
7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise
stated specifically in the specification, the term "carbocyclyl" is
meant to include carbocyclyl radicals that are optionally
substituted by one or more substituents independently selected from
alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano,
nitro, optionally substituted aryl, optionally substituted aralkyl,
optionally substituted aralkenyl, optionally substituted aralkynyl,
optionally substituted carbocyclyl, optionally substituted
carbocyclylalkyl, optionally substituted heterocyclyl, optionally
substituted heterocyclylalkyl, optionally substituted heteroaryl,
optionally substituted heteroarylalkyl, --R.sup.b--OR.sup.a,
--R.sup.b--OC(O)--R.sup.a, --R.sup.b--OC(O)--OR.sup.a,
--R.sup.b--OC(O)--N(R.sup.a).sub.2, --R.sup.b--N(R.sup.a).sub.2,
--R.sup.b--C(O) R.sup.a, --R.sup.b--C(O)OR.sup.a,
--R.sup.b--C(O)N(R.sup.a).sub.2,
--R.sup.b--O--R--C(O)N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a)C(O)OR.sup.a,
--R.sup.b--N(R.sup.a)C(O)R.sup.a,
--R.sup.b--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tOR.sup.a (where t is 1 or 2) and
--R.sup.b--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), where
each R.sup.a is independently hydrogen, alkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
fluoroalkyl, cycloalkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
aryl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), aralkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heteroaryl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl), or
heteroarylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), each R.sup.b is independently a
direct bond or a straight or branched alkylene or alkenylene chain,
and R.sup.c is a straight or branched alkylene or alkenylene chain,
and where each of the above substituents is unsubstituted unless
otherwise indicated.
"Carbocyclylalkyl" refers to a radical of the formula
--R.sup.c-carbocyclyl where R.sup.c is an alkylene chain as defined
above. The alkylene chain and the carbocyclyl radical is optionally
substituted as defined above.
"Carbocyclylalkynyl" refers to a radical of the formula
--R.sup.c-carbocyclyl where R.sup.c is an alkynylene chain as
defined above. The alkynylene chain and the carbocyclyl radical is
optionally substituted as defined above.
"Carbocyclylalkoxy" refers to a radical bonded through an oxygen
atom of the formula --O--R.sup.c-carbocyclyl where R.sup.c is an
alkylene chain as defined above. The alkylene chain and the
carbocyclyl radical is optionally substituted as defined above.
As used herein, "carboxylic acid bioisostere" refers to a
functional group or moiety that exhibits similar physical,
biological and/or chemical properties as a carboxylic acid moiety.
Examples of carboxylic acid bioisosteres include, but are not
limited to,
##STR00002## and the like.
"Halo" or "halogen" refers to bromo, chloro, fluoro or iodo
substituents.
"Fluoroalkyl" refers to an alkyl radical, as defined above, that is
substituted by one or more fluoro radicals, as defined above, for
example, trifluoromethyl, difluoromethyl, fluoromethyl,
2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.
The alkyl part of the fluoroalkyl radical may be optionally
substituted as defined above for an alkyl group.
"Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic
ring radical that comprises two to twelve carbon atoms and from one
to six heteroatoms selected from nitrogen, oxygen and sulfur.
Unless stated otherwise specifically in the specification, the
heterocyclyl radical is a monocyclic, bicyclic, tricyclic or
tetracyclic ring system, which may include fused or bridged ring
systems. The heteroatoms in the heterocyclyl radical may be
optionally oxidized. One or more nitrogen atoms, if present, are
optionally quaternized. The heterocyclyl radical is partially or
fully saturated. The heterocyclyl may be attached to the rest of
the molecule through any atom of the ring(s). Examples of such
heterocyclyl radicals include, but are not limited to, dioxolanyl,
thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,
imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,
octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,
2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,
piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,
quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,
tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,
1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated
otherwise specifically in the specification, the term
"heterocyclyl" is meant to include heterocyclyl radicals as defined
above that are optionally substituted by one or more substituents
selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo,
thioxo, cyano, nitro, optionally substituted aryl, optionally
substituted aralkyl, optionally substituted aralkenyl, optionally
substituted aralkynyl, optionally substituted carbocyclyl,
optionally substituted carbocyclylalkyl, optionally substituted
heterocyclyl, optionally substituted heterocyclylalkyl, optionally
substituted heteroaryl, optionally substituted heteroarylalkyl,
--R.sup.b--OR.sup.a, --R.sup.b--OC(O)--R.sup.a,
--R.sup.b--OC(O)--OR.sup.a, --R.sup.b--OC(O)--N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a).sub.2, --R.sup.b--C(O) R.sup.a,
--R.sup.b--C(O)OR.sup.a, --R.sup.b--C(O)N(R.sup.a).sub.2,
--R.sup.b--O--R--C(O)N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a)C(O)OR.sup.a,
--R.sup.b--N(R.sup.a)C(O)R.sup.a, --R.sup.b--N(R.sup.a)S(O),
R.sup.a (where t is 1 or 2), --R.sup.b--S(O).sub.tR.sup.a (where t
is 1 or 2), --R.sup.b--S(O).sub.tOR.sup.a (where t is 1 or 2) and
--R.sup.b--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), where
each R.sup.a is independently hydrogen, alkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
fluoroalkyl, cycloalkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
aryl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), aralkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heteroaryl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl), or
heteroarylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), each R.sup.b is independently a
direct bond or a straight or branched alkylene or alkenylene chain,
and R.sup.c is a straight or branched alkylene or alkenylene chain,
and where each of the above substituents is unsubstituted unless
otherwise indicated.
"N-heterocyclyl" or "N-attached heterocyclyl" refers to a
heterocyclyl radical as defined above containing at least one
nitrogen and where the point of attachment of the heterocyclyl
radical to the rest of the molecule is through a nitrogen atom in
the heterocyclyl radical. An N-heterocyclyl radical is optionally
substituted as described above for heterocyclyl radicals. Examples
of such N-heterocyclyl radicals include, but are not limited to,
1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl,
pyrazolidinyl, imidazolinyl, and imidazolidinyl.
"C-heterocyclyl" or "C-attached heterocyclyl" refers to a
heterocyclyl radical as defined above containing at least one
heteroatom and where the point of attachment of the heterocyclyl
radical to the rest of the molecule is through a carbon atom in the
heterocyclyl radical. A C-heterocyclyl radical is optionally
substituted as described above for heterocyclyl radicals. Examples
of such C-heterocyclyl radicals include, but are not limited to,
2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or
3-pyrrolidinyl, and the like.
"Heterocyclylalkyl" refers to a radical of the formula
--R.sup.c-heterocyclyl where R.sup.c is an alkylene chain as
defined above. If the heterocyclyl is a nitrogen-containing
heterocyclyl, the heterocyclyl is optionally attached to the alkyl
radical at the nitrogen atom. The alkylene chain of the
heterocyclylalkyl radical is optionally substituted as defined
above for an alkylene chain. The heterocyclyl part of the
heterocyclylalkyl radical is optionally substituted as defined
above for a heterocyclyl group.
"Heterocyclylalkoxy" refers to a radical bonded through an oxygen
atom of the formula --O--R.sup.c-heterocyclyl where R.sup.c is an
alkylene chain as defined above. If the heterocyclyl is a
nitrogen-containing heterocyclyl, the heterocyclyl is optionally
attached to the alkyl radical at the nitrogen atom. The alkylene
chain of the heterocyclylalkoxy radical is optionally substituted
as defined above for an alkylene chain. The heterocyclyl part of
the heterocyclylalkoxy radical is optionally substituted as defined
above for a heterocyclyl group.
"Heteroaryl" refers to a radical derived from a 3- to 18-membered
aromatic ring radical that comprises two to seventeen carbon atoms
and from one to six heteroatoms selected from nitrogen, oxygen and
sulfur. As used herein, the heteroaryl radical may be a monocyclic,
bicyclic, tricyclic or tetracyclic ring system, wherein at least
one of the rings in the ring system is fully unsaturated, i.e., it
contains a cyclic, delocalized (4n+2) .pi.-electron system in
accordance with the Huckel theory. Heteroaryl includes fused or
bridged ring systems. The heteroatom(s) in the heteroaryl radical
is optionally oxidized. One or more nitrogen atoms, if present, are
optionally quaternized. The heteroaryl is attached to the rest of
the molecule through any atom of the ring(s). Examples of
heteroaryls include, but are not limited to, azepinyl, acridinyl,
benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,
benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,
benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,
benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,
benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl,
benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl,
benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl,
cinnolinyl, cyclopenta[d]pyrimidinyl,
6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,
5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,
6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl,
dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl,
furo[3,2-c]pyridinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,
5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl,
imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl,
isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl,
5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,
1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,
oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl,
1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl,
phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,
pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl,
pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl,
pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl,
tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,
5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,
6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,
5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl,
thiadiazolyl, triazolyl, tetrazolyl, triazinyl,
thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl,
thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated
otherwise specifically in the specification, the term "heteroaryl"
is meant to include heteroaryl radicals as defined above which are
optionally substituted by one or more substituents selected from
alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl,
haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted
aryl, optionally substituted aralkyl, optionally substituted
aralkenyl, optionally substituted aralkynyl, optionally substituted
carbocyclyl, optionally substituted carbocyclylalkyl, optionally
substituted heterocyclyl, optionally substituted heterocyclylalkyl,
optionally substituted heteroaryl, optionally substituted
heteroarylalkyl, --R.sup.b--OR.sup.a, --R.sup.b--OC(O)--R.sup.a,
--R.sup.b--OC(O)--OR.sup.a, --R.sup.b--OC(O)--N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a).sub.2, --R.sup.b--C(O) R.sup.a,
--R.sup.b--C(O)OR.sup.a, --R.sup.b--C(O)N(R.sup.a).sub.2,
--R.sup.b--O--R--C(O)N(R.sup.a).sub.2,
--R.sup.b--N(R.sup.a)C(O)OR.sup.a,
--R.sup.b--N(R.sup.a)C(O)R.sup.a,
--R.sup.b--N(R.sup.a)S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tR.sup.a (where t is 1 or 2),
--R.sup.b--S(O).sub.tOR.sup.a (where t is 1 or 2) and
--R.sup.b--S(O).sub.tN(R.sup.a).sub.2 (where t is 1 or 2), where
each R.sup.a is independently hydrogen, alkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
fluoroalkyl, cycloalkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
aryl (optionally substituted with halogen, hydroxy, methoxy, or
trifluoromethyl), aralkyl (optionally substituted with halogen,
hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally
substituted with halogen, hydroxy, methoxy, or trifluoromethyl),
heterocyclylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), heteroaryl (optionally substituted
with halogen, hydroxy, methoxy, or trifluoromethyl), or
heteroarylalkyl (optionally substituted with halogen, hydroxy,
methoxy, or trifluoromethyl), each R.sup.b is independently a
direct bond or a straight or branched alkylene or alkenylene chain,
and R.sup.c is a straight or branched alkylene or alkenylene chain,
and where each of the above substituents is unsubstituted unless
otherwise indicated.
"N-heteroaryl" refers to a heteroaryl radical as defined above
containing at least one nitrogen and where the point of attachment
of the heteroaryl radical to the rest of the molecule is through a
nitrogen atom in the heteroaryl radical. An N-heteroaryl radical is
optionally substituted as described above for heteroaryl
radicals.
"C-heteroaryl" refers to a heteroaryl radical as defined above and
where the point of attachment of the heteroaryl radical to the rest
of the molecule is through a carbon atom in the heteroaryl radical.
A C-heteroaryl radical is optionally substituted as described above
for heteroaryl radicals.
"Heteroarylalkyl" refers to a radical of the formula
--R.sup.c-heteroaryl, where R.sup.c is an alkylene chain as defined
above. If the heteroaryl is a nitrogen-containing heteroaryl, the
heteroaryl is optionally attached to the alkyl radical at the
nitrogen atom. The alkylene chain of the heteroarylalkyl radical is
optionally substituted as defined above for an alkylene chain. The
heteroaryl part of the heteroarylalkyl radical is optionally
substituted as defined above for a heteroaryl group.
"Heteroarylalkoxy" refers to a radical bonded through an oxygen
atom of the formula --O--R.sup.c-heteroaryl, where R.sup.c is an
alkylene chain as defined above. If the heteroaryl is a
nitrogen-containing heteroaryl, the heteroaryl is optionally
attached to the alkyl radical at the nitrogen atom. The alkylene
chain of the heteroarylalkoxy radical is optionally substituted as
defined above for an alkylene chain. The heteroaryl part of the
heteroarylalkoxy radical is optionally substituted as defined above
for a heteroaryl group.
The compounds disclosed herein may contain one or more asymmetric
centers and may thus give rise to enantiomers, diastereomers, and
other stereoisomeric forms that may be defined, in terms of
absolute stereochemistry, as (R)- or (S)-. Unless stated otherwise,
it is intended that all stereoisomeric forms of the compounds
disclosed herein are contemplated by this disclosure. When the
compounds described herein contain alkene double bonds, and unless
specified otherwise, it is intended that this disclosure includes
both E and Z geometric isomers (e.g., cis or trans.) Likewise, all
possible isomers, as well as their racemic and optically pure
forms, and all tautomeric forms are also intended to be included.
The term "geometric isomer" refers to E or Z geometric isomers
(e.g., cis or trans) of an alkene double bond. The term "positional
isomer" refers to structural isomers around a central ring, such as
ortho-, meta-, and para-isomers around a benzene ring.
A "tautomer" refers to a molecule wherein a proton shift from one
atom of a molecule to another atom of the same molecule is
possible. The compounds presented herein may, in certain
embodiments, exist as tautomers. In circumstances where
tautomerization is possible, a chemical equilibrium of the
tautomers will exist. The exact ratio of the tautomers depends on
several factors, including physical state, temperature, solvent,
and pH. Some examples of tautomeric equilibrium include:
##STR00003##
"Optional" or "optionally" means that a subsequently described
event or circumstance may or may not occur and that the description
includes instances when the event or circumstance occurs and
instances in which it does not. For example, "optionally
substituted aryl" means that the aryl radical may or may not be
substituted and that the description includes both substituted aryl
radicals and aryl radicals having no substitution.
"Pharmaceutically acceptable salt" includes both acid and base
addition salts. A pharmaceutically acceptable salt of any one of
the substituted heterocyclic derivative compounds described herein
is intended to encompass any and all pharmaceutically suitable salt
forms. Preferred pharmaceutically acceptable salts of the compounds
described herein are pharmaceutically acceptable acid addition
salts and pharmaceutically acceptable base addition salts.
"Pharmaceutically acceptable acid addition salt" refers to those
salts which retain the biological effectiveness and properties of
the free bases, which are not biologically or otherwise
undesirable, and which are formed with inorganic acids such as
hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,
phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous
acid, and the like. Also included are salts that are formed with
organic acids such as aliphatic mono- and dicarboxylic acids,
phenyl-substituted alkanoic acids, hydroxy alkanoic acids,
alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic
acids, etc. and include, for example, acetic acid, trifluoroacetic
acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid,
maleic acid, malonic acid, succinic acid, fumaric acid, tartaric
acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,
salicylic acid, and the like. Exemplary salts thus include
sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates,
phosphates, monohydrogenphosphates, dihydrogenphosphates,
metaphosphates, pyrophosphates, chlorides, bromides, iodides,
acetates, trifluoroacetates, propionates, caprylates, isobutyrates,
oxalates, malonates, succinate suberates, sebacates, fumarates,
maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates,
dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,
phenylacetates, citrates, lactates, malates, tartrates,
methanesulfonates, and the like. Also contemplated are salts of
amino acids, such as arginates, gluconates, and galacturonates
(see, for example, Berge S. M. et aL, "Pharmaceutical Salts,"
Journal of Pharmaceutical Science, 66:1-19 (1997), which is hereby
incorporated by reference in its entirety). Acid addition salts of
basic compounds may be prepared by contacting the free base forms
with a sufficient amount of the desired acid to produce the salt
according to methods and techniques with which a skilled artisan is
familiar.
"Pharmaceutically acceptable base addition salt" refers to those
salts that retain the biological effectiveness and properties of
the free acids, which are not biologically or otherwise
undesirable. These salts are prepared from addition of an inorganic
base or an organic base to the free acid. Pharmaceutically
acceptable base addition salts may be formed with metals or amines,
such as alkali and alkaline earth metals or organic amines. Salts
derived from inorganic bases include, but are not limited to,
sodium, potassium, lithium, ammonium, calcium, magnesium, iron,
zinc, copper, manganese, aluminum salts and the like. Salts derived
from organic bases include, but are not limited to, salts of
primary, secondary, and tertiary amines, substituted amines
including naturally occurring substituted amines, cyclic amines and
basic ion exchange resins, for example, isopropylamine,
trimethylamine, diethylamine, triethylamine, tripropylamine,
ethanolamine, diethanolamine, 2-dimethylaminoethanol,
2-diethylaminoethanol, dicyclohexylamine, lysine, arginine,
histidine, caffeine, procaine, N,N-dibenzylethylenediamine,
chloroprocaine, hydrabamine, choline, betaine, ethylenediamine,
ethylenedianiline, N-methylglucamine, glucosamine, methylglucamine,
theobromine, purines, piperazine, piperidine, N-ethylpiperidine,
polyamine resins and the like. See Berge et al., supra.
As used herein, "treatment" or "treating," or "palliating" or
"ameliorating" are used interchangeably herein. These terms refers
to an approach for obtaining beneficial or desired results
including but not limited to therapeutic benefit and/or a
prophylactic benefit. By "therapeutic benefit" is meant eradication
or amelioration of the underlying disorder being treated. Also, a
therapeutic benefit is achieved with the eradication or
amelioration of one or more of the physiological symptoms
associated with the underlying disorder such that an improvement is
observed in the patient, notwithstanding that the patient may still
be afflicted with the underlying disorder. For prophylactic
benefit, the compositions may be administered to a patient at risk
of developing a particular disease, or to a patient reporting one
or more of the physiological symptoms of a disease, even though a
diagnosis of this disease may not have been made.
"Prodrug" is meant to indicate a compound that may be converted
under physiological conditions or by solvolysis to a biologically
active compound described herein. Thus, the term "prodrug" refers
to a precursor of a biologically active compound that is
pharmaceutically acceptable. A prodrug may be inactive when
administered to a subject, but is converted in vivo to an active
compound, for example, by hydrolysis. The prodrug compound often
offers advantages of solubility, tissue compatibility or delayed
release in a mammalian organism (see, e.g., Bundgard, H., Design of
Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
A discussion of prodrugs is provided in Higuchi, T., et al.,
"Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series,
Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward
B. Roche, American Pharmaceutical Association and Pergamon Press,
1987, both of which are incorporated in full by reference
herein.
The term "prodrug" is also meant to include any covalently bonded
carriers, which release the active compound in vivo when such
prodrug is administered to a mammalian subject. Prodrugs of an
active compound, as described herein, may be prepared by modifying
functional groups present in the active compound in such a way that
the modifications are cleaved, either in routine manipulation or in
vivo, to the parent active compound. Prodrugs include compounds
wherein a hydroxy, amino or mercapto group is bonded to any group
that, when the prodrug of the active compound is administered to a
mammalian subject, cleaves to form a free hydroxy, free amino or
free mercapto group, respectively. Examples of prodrugs include,
but are not limited to, acetate, formate and benzoate derivatives
of alcohol or amine functional groups in the active compounds and
the like.
Substituted Heterocyclic Derivative Compounds
Substituted heterocyclic derivative compounds are described herein
that are lysine specific demethylase-1 inhibitors. These compounds,
and compositions comprising these compounds, are useful for the
treatment of cancer and neoplastic disease. The compounds described
herein are useful for treating prostate cancer, breast cancer,
bladder cancer, lung cancer and/or melanoma and the like.
One embodiment provides a compound having the structure of Formula
(I), or a pharmaceutically acceptable salt thereof,
##STR00004##
wherein, A is C; B is N; and D is --R.sup.3; or A is N; B is C; and
D is N; each R.sup.3 is independently chosen from hydrogen or
optionally substituted alkyl; W.sup.1 and W.sup.2 are independently
chosen from N, C--H, or C--F; X is chosen from optionally
substituted aryl, optionally substituted heteroaryl, optionally
substituted cycloalkyl, optionally substituted alkyl, optionally
substituted heterocyclyl, optionally substituted cycloalkylalkyl,
optionally substituted heterocyclylalkyl, optionally substituted
aralkyl, or optionally substituted heteroarylalkyl; Y is chosen
from hydrogen, halogen, optionally substituted alkyl, optionally
substituted cycloalkyl, or optionally substituted cycloalkylalkyl;
and Z is chosen from an optionally substituted N-heterocyclyl,
optionally substituted --N(H)-heterocyclylalkyl, optionally
substituted --N(Me)-heterocyclylalkyl, or --N(R.sup.3).sub.2.
Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein A is N; B is C; and D is
N.
Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein A is C; B is N; and D is
C--R.sup.3.
Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein A is C; B is N; and D is
C--R.sup.3, and R.sup.3 is hydrogen.
Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein A is C; B is N; and D is
C--R.sup.3, and R.sup.3 is optionally substituted alkyl.
Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein W.sup.2 is C--H. Another
embodiment provides the compound or pharmaceutically acceptable
salt of Formula (I), wherein W.sup.1 is C--F. Another embodiment
provides the compound or pharmaceutically acceptable salt of
Formula (I), wherein W.sup.1 is C--H. Another embodiment provides
the compound or pharmaceutically acceptable salt of Formula (I),
wherein W.sup.1 is N.
Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein X is optionally substituted
aryl. Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein X is optionally substituted
aryl and the optionally substituted aryl is an optionally
substituted phenyl.
Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein X is optionally substituted
heteroaryl. Another embodiment provides the compound or
pharmaceutically acceptable salt of Formula (I), wherein X is
optionally substituted heteroaryl and the optionally substituted
heteroaryl is chosen from an optionally substituted pyridinyl,
optionally substituted pyrimidinyl, optionally substituted
pyrazinyl, optionally substituted pyrazolyl, optionally substituted
indazolyl, optionally substituted azaindazolyl, optionally
substituted isoindazolyl, optionally substituted indolyl, or
optionally substituted azaindolyl.
Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein Z is an optionally
substituted N-heterocyclyl. Another embodiment provides the
compound or pharmaceutically acceptable salt of Formula (I),
wherein Z is an optionally substituted N-heterocyclyl and the
optionally substituted N-heterocyclyl is a 4-, 5-, 6-, or
7-membered N-heterocyclyl. Another embodiment provides the compound
or pharmaceutically acceptable salt of Formula (I), wherein Z is an
optionally substituted N-heterocyclyl, and the optionally
substituted N-heterocyclyl is a 6-membered N-heterocyclyl. Another
embodiment provides the compound or pharmaceutically acceptable
salt of Formula (I), wherein Z is an optionally substituted
N-heterocyclyl, the optionally substituted N-heterocyclyl is an
optionally substituted piperidine. Another embodiment provides the
compound or pharmaceutically acceptable salt of Formula (I),
wherein Z is an optionally substituted N-heterocyclyl, the
optionally substituted N-heterocyclyl is an optionally substituted
piperidine, and the optionally substituted piperidine is an
optionally substituted 3-aminopiperidine. Another embodiment
provides the compound or pharmaceutically acceptable salt of
Formula (I), wherein Z is an optionally substituted N-heterocyclyl
and the optionally substituted N-heterocyclyl is a 5-membered
N-heterocyclyl. Another embodiment provides the compound or
pharmaceutically acceptable salt of Formula (I), wherein Z is an
optionally substituted N-heterocyclyl, and the optionally
substituted N-heterocyclyl is an optionally substituted
pyrrolidine. Another embodiment provides the compound or
pharmaceutically acceptable salt of Formula (I), wherein Z is an
optionally substituted N-heterocyclyl, the optionally substituted
N-heterocyclyl is an optionally substituted pyrrolidine and the
optionally substituted pyrrolidine is an optionally substituted
3-aminopyrrolidine.
Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein Y is hydrogen. Another
embodiment provides the compound or pharmaceutically acceptable
salt of Formula (I), wherein Y is halogen.
Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein Y is optionally substituted
alkyl. Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein Y is optionally substituted
alkyl, and the optionally substituted alkyl is an optionally
substituted C.sub.1-C.sub.3 alkyl. Another embodiment provides the
compound or pharmaceutically acceptable salt of Formula (I),
wherein Y is optionally substituted alkyl, and the optionally
substituted alkyl is an optionally substituted C.sub.1 alkyl.
Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein Y is optionally substituted
alkyl, and the optionally substituted alkyl is a methyl group.
Another embodiment provides the compound or pharmaceutically
acceptable salt of Formula (I), wherein Y is optionally substituted
cycloalkyl. Another embodiment provides the compound or
pharmaceutically acceptable salt of Formula (I), wherein Y is
optionally substituted cycloalkylalkyl.
In some embodiments, the substituted heterocyclic derivative
compound described herein has the structure provided in Table
1.
TABLE-US-00001 TABLE 1 Chemical Synthesis Example Structure Name 1
##STR00005## 4-[5-(3-(R)-amino-piperidine-1-
carbonyl)-1-methyl-2-p-tolyl-1H- pyrrol-3-yl]-benzonitrile 2
##STR00006## 4-[5-(3-(R)-amino-piperidine-1-
carbonyl)-2-(4-methoxy-phenyl)-1- methyl-1H-pyrrol-3-yl]-2-fluoro-
benzonitrile 3 ##STR00007## 4-[5-(3-(R)-amino-piperidine-1-
carbonyl)-1-(2-hydroxy-ethyl)-2-p-
tolyl-1H-pyrrol-3-yl]-benzonitrile 4 ##STR00008##
4-[5-(3-(R)-amino-piperidine-1- carbonyl)-1-(2-hydroxy-ethyl)-2-p-
tolyl-1H-pyrrol-3-yl]-2-fluoro- benzonitrile 5 ##STR00009##
4-[5-(3-(R)-amino-piperidine-1- carbonyl)-1-methyl-2-(6-methyl-
pyridin-3-yl)-1H-pyrrol-3-yl]- benzonitrile 6 ##STR00010##
4-[5-(3-(R)-amino-piperidine-1- carbonyl)-1-methyl-2-pyridin-4-yl-
1H-pyrrol-3-yl]-benzonitrile 7 ##STR00011##
4-[5-(3-(R)-amino-piperidine-1- carbonyl)-1-(2-hydroxy-ethyl)-2-(4-
methoxy-phenyl)-1H-pyrrol-3-yl]- benzonitrile 8 ##STR00012##
4-[5-(3-(R)-amino-piperidine-1- carbonyl)-1-(2-hydroxy-ethyl)-2-(4-
methoxy-phenyl)-1H-pyrrol-3-yl]-2- fluoro-benzonitrile 9
##STR00013## 4-[5-(3-(R)-amino-piperidine-1-
carbonyl)-1-(3-hydroxy-propyl)-2-(4-
methoxy-phenyl)-1H-pyrrol-3-yl]-2- fluoro-benzonitrile 10
##STR00014## 4-[5-(3-(R)-amino-piperidine-1-
carbonyl)-1-methyl-2-(1-methyl-1H-
benzoimidazol-5-yl)-1H-pyrrol-3-yl]- 2-fluoro-benzonitrile 11
##STR00015## 4-[4-[(3R)-3-aminopiperidine-1-
carbonyl]-5-methyl-1-(4- methylphenyl)imidazol-2- yl]benzonitrile
12 ##STR00016## 4-[4-[(3R)-3-aminopiperidine-1-
carbonyl]-1-(4-methoxyphenyl)-5- methylimidazol-2-yl]-2-
fluorobenzonitrile 13 ##STR00017## 4-[4-[(3R)-3-aminopyrrolidine-1-
carbonyl]-1-(4-methoxyphenyl)-5- methylimidazol-2-yl]-2-
fluorobenzonitrile 14 ##STR00018## 4-[4-[(3S)-3-aminopyrrolidine-1-
carbonyl]-1-(4-methoxyphenyl)-5- methylimidazol-2-yl]-2-
fluorobenzonitrile 15 ##STR00019## 4-[4-[(3R)-3-aminopiperidine-1-
carbonyl]-1-(6-methoxypyridin-3-yl)- 5-methylimidazol-2-yl]-2-
fluorobenzonitrile 16 ##STR00020## 4-[4-[(3R)-3-aminopiperidine-1-
carbonyl]-1-(3-fluoro-4- methoxyphenyl)-5-methylimidazol-2-
yl]-2-fluorobenzonitrile 17 ##STR00021##
4-[4-[(3S)-3-aminopiperidine-1- carbonyl]-1-(3-fluoro-4-
methoxyphenyl)-5-methylimidazol-2- yl]-2-fluorobenzonitrile 18
##STR00022## 4-[4-[(3S)-3-aminopyrrolidine-1-
carbonyl]-1-(3-fluoro-4- methoxyphenyl)-5-methylimidazol-2-
yl]-2-fluorobenzonitrile 19 ##STR00023##
4-[4-[(3R)-3-aminopiperidine-1- carbonyl]-1-(3-fluoro-4-
methoxyphenyl)imidazol-2-yl]-2- fluorobenzonitrile 20 ##STR00024##
4-[4-[(3S)-3-aminopyrrolidine-1- carbonyl]-1-(3-fluoro-4-
methoxyphenyl)imidazol-2-yl]-2- fluorobenzonitrile 21 ##STR00025##
4-[4-[(3R)-3-aminopiperidine-1- carbonyl]-5-methyl-1-(2-
methylindazol-5-yl)imidazol-2-yl]-2- fluorobenzonitrile 22
##STR00026## 4-[4-[(3S)-3-aminopyrrolidine-1-
carbonyl]-5-methyl-1-(2- methylindazol-5-yl)imidazol-2-yl]-2-
fluorobenzonitrile 23 ##STR00027## 4-[4-[(3R)-3-aminopiperidine-1-
carbonyl]-5-methyl-1-(1- methylindazol-5-yl)imidazol-2-yl]-2-
fluorobenzonitrile 24 ##STR00028## 4-[4-[(3S)-3-aminopyrrolidine-1-
carbonyl]-5-methyl-1-(1- methylindazol-5-yl)imidazol-2-yl]-2-
fluorobenzonitrile 25 ##STR00029## 4-[4-[(3R)-3-aminopiperidine-1-
carbonyl]-1-(2-methylindazol-5- yl)imidazol-2-yl]-2-
fluorobenzonitrile 26 ##STR00030## 4-[4-[(3S)-3-aminopyrrolidine-1-
carbonyl]-1-(2-methylindazol-5- yl)imidazol-2-yl]-2-
fluorobenzonitrile 27 ##STR00031## 4-[4-[(3R)-3-aminopiperidine-1-
carbonyl]-1-(1-methylindazol-5- yl)imidazol-2-yl]-2-
fluorobenzonitrile 28 ##STR00032## 4-[4-[(3S)-3-aminopyrrolidine-1-
carbonyl]-1-(1-methylindazol-5- yl)imidazol-2-yl]-2-
fluorobenzonitrile 29 ##STR00033## 4-{5-[((3R)-3-
aminopiperidyl)carbonyl]-1-methyl-
2-(2-methyl(2H-indazol-5-yl))pyrrol-
3-yl}-2-fluorobenzenecarbonitrile 30 ##STR00034##
N-((3R)pyrrolidin-3-yl)[4-(4-cyano- 3-fluorophenyl)-1-methyl-5-(2-
methyl(2H-indazol-5-yl))pyrrol-2- yl]carboxamide 31 ##STR00035##
N-(2-aminoethyl)[4-(4-cyano-3- fluorophenyl)-1-methyl-5-(2-
methyl(2H-indazol-5-yl))pyrrol-2- yl]-N-methylcarboxamide 32
##STR00036## [4-(4-cyano-3-fluorophenyl)-1-
methyl-5-(2-methyl(2H-indazol-5- yl))pyrrol-2-yl]-N-[2-
(methylamino)ethyl]carboxamide 33 ##STR00037##
N-[((3S)pyrrolidin-3-yl)methyl][4-(4-
cyano-3-fluorophenyl)-1-methyl-5-
(2-methyl(2H-indazol-5-yl))pyrrol-2- yl]carboxamide 34 ##STR00038##
(R)-4-(5-(3-aminopiperidine-1- carbonyl)-1-(3-hydroxypropyl)-2-(2-
methyl-2H-indazol-5-yl)-1H-pyrrol- 3-yl)-2-fluorobenzonitrile 35
##STR00039## (R)-4-(5-(3-aminopiperidine-1-
carbonyl)-1-(2-hydroxyethyl)-2-(2-
methyl-2H-indazol-5-yl)-1H-pyrrol- 3-yl)-2-fluorobenzonitrile 36
##STR00040## (R)-4-(5-(3-aminopiperidine-1-
carbonyl)-1-(2-methoxyethyl)-2-(2-
methyl-2H-indazol-5-yl)-1H-pyrrol- 3-yl)-2-fluorobenzonitrile 37
##STR00041## (R)-2-(5-(3-aminopiperidine-1- carbonyl)-3-(4-cyano-3-
fluorophenyl)-2-(4-methoxyphenyl)- 1H-pyrrol-1-yl)acetamide 38
##STR00042## 4-(5-((R)-3-aminopiperidine-1- carbonyl)-1-((R)-2,3-
dihydroxypropyl)-2-(2-methyl-2H- indazol-5-yl)-1H-pyrrol-3-yl)-2-
fluorobenzonitrile 39 ##STR00043## 4-(5-((R)-3-aminopiperidine-1-
carbonyl)-1-((S)-2,3- dihydroxypropyl)-2-(2-methyl-2H-
indazol-5-yl)-1H-pyrrol-3-yl)-2- fluorobenzonitrile 40 ##STR00044##
N-[((3R)pyrrolidin-3-yl)methyl][4-
(4-cyano-3-fluorophenyl)-1-methyl-
5-(2-methyl(2H-indazol-5-yl))pyrrol- 2-yl]carboxamide 41
##STR00045## 4-{5-[((3R)-3- aminopiperidyl)carbonyl]-3-(4-
cyano-3-fluorophenyl)-2-(4- methoxyphenyl)pyrrolyl}butanoic acid 42
##STR00046## 4-{5-[((3R)-3- aminopiperidyl)carbonyl]-3-(4-
cyano-3-fluorophenyl)-2-(4- methoxyphenyl)pyrrolyl}butanamide 43
##STR00047## 4-[4-(4-Aminopiperidine-1- carbonyl)-5-methyl-1-(2-
methylindazol-5-yl)imidazol-2-yl]-2- fluorobenzonitrile 44
##STR00048## N-(2-Aminoethyl)-2-(4-cyano-3-
fluorophenyl)-N,5-dimethyl-1-(2- methylindazol-5-yl)imidazole-4-
carboxamide 45 ##STR00049## 2-(4-Cyano-3-fluorophenyl)-5-
methyl-1-(2-methylindazol-5-yl)-N- piperidin-3-ylimidazole-4-
carboxamide 46 ##STR00050## 2-(4-Cyano-3-fluorophenyl)-5-
methyl-1-(2-methylindazol-5-yl)-N- pyrrolidin-3-ylimidazole-4-
carboxamide 47 ##STR00051## 4-[4-[(3R)-3-Aminopiperidine-1-
carbonyl]-1-(6-fluoro-2- methylindazol-5-yl)-5-
methylimidazol-2-yl]-2- fluorobenzonitrile 48 ##STR00052##
4-[4-[(3S)-3- (Dimethylamino)pyrrolidine-1-
carbonyl]-1-(6-fluoro-2- methylindazol-5-yl)-5-
methylimidazol-2-yl]-2- fluorobenzonitrile 49 ##STR00053##
2-Fluoro-4-[1-(6-fluoro-2- methylindazol-5-yl)-5-methyl-4-
[(3S)-3-(methylamino)pyrrolidine-1-
carbonyl]imidazol-2-yl]benzonitrile 50 ##STR00054##
4-[4-[(3S)-3-Aminopyrrolidine-1- carbonyl]-1-(7-fluoro-2-
methylindazol-5-yl)-5- methylimidazol-2-yl]-2- fluorobenzonitrile
51 ##STR00055## 2-Fluoro-4-[1-(7-fluoro-2-
methylindazol-5-yl)-5-methyl-4- [(3S)-3-(methylamino)pyrrolidine-1-
carbonyl]imidazol-2-yl]benzonitrile 52 ##STR00056## 4-[4-[(3S)-3-
(Dimethylamino)pyrrolidine-1- carbonyl]-1-(7-fluoro-2-
methylindazol-5-yl)-5- methylimidazol-2-yl]-2- fluorobenzonitrile
53 ##STR00057## 4-[4-[(3R)-3-Aminopiperidine-1-
carbonyl]-1-(3-chloro-2- methylindazol-5-yl)-5-
methylimidazol-2-yl]-2- fluorobenzonitrile 54 ##STR00058##
4-[1-(3-Chloro-2-methylindazol-5- yl)-5-methyl-4-[(3S)-3-
(methylamino)pyrrolidine-1- carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 55 ##STR00059##
4-[1-(3-Chloro-2-methylindazol-5- yl)-5-methyl-4-[(3R)-3-
(methylamino)piperidine-1- carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 56 ##STR00060##
1-(3-Chloro-2-methylindazol-5-yl)-2-
(4-cyano-3-fluorophenyl)-5-methyl- N-[(3R)-1-methylpiperidin-3-
yl]imidazole-4-carboxamide 57 ##STR00061##
4-[1-(3-Chloro-2-methylindazol-5- yl)-4-[(3S)-3-
(dimethylamino)pyrrolidine-1- carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 58 ##STR00062##
4-[1-(3-Chloro-2-methylindazol-5- yl)-4-[(3S)-3-
(dimethylamino)pyrrolidine-1- carbonyl]-5-fluoroimidazol-2-yl]-2-
fluorobenzonitrile 59 ##STR00063##
1-(3-Chloro-2-methylindazol-5-yl)-2-
(4-cyano-3fluorophenyl)-N-[(3R)-1-
methylpiperidin-3-yl]imidazole-4- carboxamide 60 ##STR00064##
2-(4-Cyano-3-fluorophenyl)-5- methyl-1-(2-methylindazol-5-yl)-N-
[(3R)-1-methylpiperidin-3- yl]imidazole-4-carboxamide 61
##STR00065## 4-[4-[(3R)-3-Aminopiperidine-1-
carbonyl]-1-(3-chloro-2- methylindazol-5-yl)-5-
fluoroimidazol-2-yl]-2- fluorobenzonitrile 62 ##STR00066##
2-(4-Cyano-3-fluorophenyl)-1-(3- fluoro-4-methoxyphenyl)-5-methyl-
N-[(3R)-piperidin-3-yl]imidazole-4- carboxamide 63 ##STR00067##
2-(4-Cyano-3-fluorophenyl)-1-(3- fluoro-4-methoxyphenyl)-5-methyl-
N-[(3S)-piperidin-3-yl]imidazole-4- carboxamide 64 ##STR00068##
2-Fluoro-4-[1-(3-fluoro-4- methoxyphenyl)-5-methyl-4-[(3S)-3-
(methylamino)pyrrolidine-1- carbonyl]imidazol-2-yl]benzonitrile 65
##STR00069## 2-Fluoro-4-[1-(3-fluoro-4-
methoxyphenyl)-4-[(3S)-3-
(methylamino)pyrrolidine-1- carbonyl]imidazol-2-yl]benzonitrile 66
##STR00070## 4-[4-[(3R)-3-Aminopiperidine-1-
carbonyl]-5-chloro-1-(3-fluoro-4- methoxyphenyl)imidazol-2-yl]-2-
fluorobenzonitrile 67 ##STR00071## 4-[4-[(3R)-3-Aminopiperidine-1-
carbonyl]-5-fluoro-1-(3-fluoro-4- methoxyphenyl)imidazol-2-yl]-2-
fluorobenzonitrile 68 ##STR00072##
2-Fluoro-4-[5-fluoro-1-(3-fluoro-4- methoxyphenyl)-4-[(3S)-3-
(methylamino)pyrrolidine-1- carbonyl]imidazol-2-yl]benzonitrile 69
##STR00073## 2-Fluoro-4-[1-(4-methoxyphenyl)-5- methyl-4-[(3S)-3-
(methylamino)pyrrolidine-1- carbonyl]imidazol-2-yl]benzonitrile 70
##STR00074## 2-Fluoro-4-[1-(4-methoxyphenyl)-5- methyl-4-[(3R)-3-
(methylamino)piperidine-1- carbonyl]imidazol-2-yl]benzonitrile 71
##STR00075## 2-Fluoro-4-[1-(4-methoxyphenyl)-4-
[(3S)-3-(methylamino)pyrrolidine-1-
carbonyl]imidazol-2-yl]benzonitrile 72 ##STR00076##
2-Fluoro-4-[1-(4-methoxyphenyl)-4-
[(3R)-3-(methylamino)piperidine-1-
carbonyl]imidazol-2-yl]benzonitrile 73 ##STR00077##
2-Fluoro-4-[5-fluoro-1-(4- methoxyphenyl)-4-[(3S)-3-
(methylamino)pyrrolidine-1- carbonyl]imidazol-2-yl]benzonitrile 74
##STR00078## 2-Fluoro-4-[5-fluoro-1-(4- methoxyphenyl)-4-[(3R)-3-
(methylamino)piperidine-1- carbonyl]imidazol-2-yl]benzonitrile 75
##STR00079## 4-[4-[(3R)-3-Aminopiperidine-1-
carbonyl]-5-chloro-1-(2- methylindazol-5-yl)imidazol-2-yl]-2-
fluorobenzonitrile 76 ##STR00080## 4-[4-[(3R)-3-Aminopiperidine-1-
carbonyl]-5-chloro-1-(3-chloro-2-
methylindazol-5-yl)imidazol-2-yl]-2- fluorobenzonitrile 77
##STR00081## 4-[4-[(3R)-3-Aminopiperidine-1-
carbonyl]-5-fluoro-1-(2- methylindazol-5-yl)imidazol-2-yl]-2-
fluorobenzonitrile 78 ##STR00082## 4-[4-[(3R)-3-Aminopiperidine-1-
carbonyl]-1-(6-cyclopropylpyridin-3- yl)-5-methylimidazol-2-yl]-2-
fluorobenzonitrile 79 ##STR00083## 4-[4-[(3S)-3-Aminopyrrolidine-1-
carbonyl]-1-(6-cyclopropylpyridin-3- yl)-5-methylimidazol-2-yl]-2-
fluorobenzonitrile 80 ##STR00084## 4-[4-[(3R)-3-Aminopiperidine-1-
carbonyl]-5-chloro-1-(6- cyclopropylpyridin-3-yl)imidazol-2-
yl]-2-fluorobenzonitrile 81 ##STR00085##
4-[4-[(3S)-3-Aminopyrrolidine-1- carbonyl]-5-chloro-1-(6-
cyclopropylpyridin-3-yl)imidazol-2- yl]-2-fluorobenzonitrile 82
##STR00086## 2-(4-Cyano-3-fluorophenyl)-1-(3-
fluoro-4-methoxyphenyl)-5-methyl-
N-[(3R)-pyrrolidin-3-yl]imidazole-4- carboxamide 83 ##STR00087##
2-(4-Cyano-3-fluorophenyl)-1-(3- fluoro-4-methoxyphenyl)-5-methyl-
N-[(3S)-pyrrolidin-3-yl]imidazole-4- carboxamide 84 ##STR00088##
5-Chloro-2-(4-cyano-3- fluorophenyl)-1-(3-fluoro-4-
methoxyphenyl)-N-[(3R)-piperidin- 3-yl]imidazole-4-carboxamide 85
##STR00089## 5-Chloro-2-(4-cyano-3- fluorophenyl)-1-(3-fluoro-4-
methoxyphenyl)-N-[(3S)-piperidin-3- yl]imidazole-4-carboxamide 86
##STR00090## 2-(4-Cyano-3-fluorophenyl)-5- fluoro-1-(3-fluoro-4-
methoxyphenyl)-N-[(3R)-piperidin- 3-yl]imidazole-4-carboxamide 87
##STR00091## 2-(4-Cyano-3-fluorophenyl)-1-(3-
fluoro-4-methoxyphenyl)-5-methyl- N-piperidin-4-ylimidazole-4-
carboxamide 88 ##STR00092## 4-[4-[3-(Aminomethyl)azetidine-1-
carbonyl]-1-(3-fluoro-4- methoxyphenyl)-5-methylimidazol-2-
yl]-2-fluorobenzonitrile 89 ##STR00093##
4-[4-[(3S)-3-Aminopyrrolidine-1- carbonyl]-5-fluoro-1-(3-fluoro-4-
methoxyphenyl)imidazol-2-yl]-2- fluorobenzonitrile 90 ##STR00094##
4-[4-(1,7-Diazaspiro[4.4]nonane-7- carbonyl)-5-methyl-1-(2-
methylindazol-5-yl)imidazol-2-yl]-2- fluorobenzonitrile 91
##STR00095## 4-[4-(2,6-Diazaspiro[3.4]octane-6-
carbonyl)-5-methyl-1-(2- methylindazol-5-yl)imidazol-2-yl]-2-
fluorobenzonitrile 92 ##STR00096##
4-[4-(1,7-Diazaspiro[3.4]octane-7- carbonyl)-5-methyl-1-(1-
methylindazol-5-yl)imidazol-2-yl]-2- fluorobenzonitrile 93
##STR00097## 4-[1-(3-Chloro-2-methylindazol-5-
yl)-4-(1,7-diazaspiro[3.4]octane-7- carbonyl)imidazol-2-yl]-2-
fluorobenzonitrile 94 ##STR00098## 4-[4-[(3S)-3-
(Dimethylamino)pyrrolidine-1- carbonyl]-5-methyl-1-(2-
methylindazol-5-yl)imidazol-2-yl]-2- fluorobenzonitrile 95
##STR00099## 4-[4-[(3S)-3- (Dimethylamino)pyrrolidine-1-
carbonyl]-5-methyl-1-(1- methylindazol-5-yl)imidazol-2-yl]-2-
fluorobenzonitrile 96 ##STR00100##
4-[1-(3-Chloro-2-methylindazol-5- yl)-4-[(3S)-3-
(dimethylamino)pyrrolidine-1- carbonyl]-5-methylimidazol-2-yl]-2-
fluorobenzonitrile 97 ##STR00101## 2-Fluoro-4-[5-methyl-4-[(3S)-3-
(methylamino)piperidine-1- carbonyl]-1-(2-methylindazol-5-
yl)imidazol-2-yl]benzonitrile 98 ##STR00102##
2-Fluoro-4-[5-methyl-4-[(3R)-3- (methylamino)piperidine-1-
carbonyl]-1-(2-methylindazol-5- yl)imidazol-2-yl]benzonitrile 99
##STR00103## 4-[4-[(3S)-3- (Dimethylamino)pyrrolidine-1-
carbonyl]-1-(2-methylindazol-5- yl)imidazol-2-yl]-2-
fluorobenzonitrile 100 ##STR00104## 4-[5-Chloro-4-[(3S)-3-
(dimethylamino)pyrrolidine-1- carbonyl]-1-(2-methylindazol-5-
yl)imidazol-2-yl]-2- fluorobenzonitrile 101 ##STR00105##
4-[5-Chloro-1-(3-chloro-2- methylindazol-5-yl)-4-[(3S)-3-
(dimethylamino)pyrrolidine-1- carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 102 ##STR00106## 4-[4-[(3S)-3-
(Dimethylamino)pyrrolidine-1- carbonyl]-1-(2,3-dimethylindazol-5-
yl)-5-methylimidazol-2-yl]-2- fluorobenzonitrile 103 ##STR00107##
4-[1-(2,3-Dimethylindazol-5-yl)-5- methyl-4-[(3S)-3-
(methylamino)pyrrolidine-1- carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 104 ##STR00108##
2-(4-Cyano-3-fluorophenyl)-1-(2,3-
dimethylindazol-5-yl)-5-methyl-N- [(3R)-piperidin-3-yl]imidazole-4-
carboxamide 105 ##STR00109## 4-[1-(2,3-Dimethylindazol-5-yl)-5-
methyl-4-[(3R)-3- (methylamino)piperidine-1-
carbonyl]imidazol-2-yl]-2- fluorobenzonitrile 106 ##STR00110##
1-(3-Chloro-2-methylindazol-5-yl)-2-
(4-cyano-3-fluorophenyl)-N-[(3R)-1-
methylpyrrolidin-3-yl]imidazole-4- carboxamide 107 ##STR00111##
1-(3-Chloro-2-methylindazol-5-yl)-2-
(4-cyano-3-fluorophenyl)-N-[(3S)-1-
methylpyrrolidin-3-yl]imidazole-4- carboxamide 108 ##STR00112##
2-(4-Cyano-3-fluorophenyl)-5- methyl-1-(2-methylindazol-5-yl)-N-
[(3R)-1-methylpyrrolidin-3- yl]imidazole-4-carboxamide 109
##STR00113## 2-(4-Cyano-3-fluorophenyl)-5-
methyl-1-(2-methylindazol-5-yl)-N- [(3S)-1-methylpyrrolidin-3-
yl]imidazole-4-carboxamide 110 ##STR00114##
4-[1-(3-Chloro-6-fluoro-2- methylindazol-5-yl)-4-[(3S)-3-
(dimethylamino)pyrrolidine-1- carbonyl]-5-methylimidazol-2-yl]-2-
fluorobenzonitrile 111 ##STR00115## 4-[1-(3-Chloro-6-fluoro-2-
methylindazol-5-yl)-5-methyl-4- [(3S)-3-(methylamino)pyrrolidine-1-
carbonyl]imidazol-2-yl]-2- fluorobenzonitrile 112 ##STR00116##
4-[1-(3-Chloro-6-fluoro-2- methylindazol-5-yl)-4-[(3S)-3-
(dimethylamino)pyrrolidine-1- carbonyl]-5-methylimidazol-2-yl]-2-
fluorobenzonitrile 113 ##STR00117##
4-[1-(3-Chloro-2-methylindazol-5- yl)-4-[(3S)-3-
(methylamino)pyrrolidine-1- carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 114 ##STR00118##
1-(3-Chloro-2-methylindazol-5-yl)-2-
(4-cyano-3-fluorophenyl)-N-[(3R)- piperidin-3-yl]imidazole-4-
carboxamide 115 ##STR00119## 4-[1-(3-Chloro-2-methylindazol-5-
yl)-4-[(3R)-3- (methylamino)piperidine-1-
carbonyl]imidazol-2-yl]-2- fluorobenzonitrile 116 ##STR00120##
4-[1-(3-Chloro-2-methylindazol-5- yl)-4-[(3S)-3-
(methylamino)piperidine-1- carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 117 ##STR00121##
1-(3-Chloro-2-methylindazol-5-yl)-2-
(4-cyano-3-fluorophenyl)-5-methyl-
N-[(3R)-piperidin-3-yl]imidazole-4- carboxamide 118 ##STR00122##
4-[1-(3-Chloro-2-methylindazol-5- yl)-5-methyl-4-[(3S)-3-
(methylamino)piperidine-1- carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile
In some embodiments, the substituted heterocyclic derivative
compound described herein has the structure provided in Table
2.
TABLE-US-00002 TABLE 2 ##STR00123## ##STR00124## ##STR00125##
##STR00126## ##STR00127## ##STR00128## ##STR00129## ##STR00130##
##STR00131## ##STR00132## ##STR00133## ##STR00134## ##STR00135##
##STR00136## ##STR00137## ##STR00138## ##STR00139## ##STR00140##
##STR00141## ##STR00142## ##STR00143## ##STR00144## ##STR00145##
##STR00146## ##STR00147## ##STR00148## ##STR00149## ##STR00150##
##STR00151## ##STR00152## ##STR00153## ##STR00154## ##STR00155##
##STR00156## ##STR00157## ##STR00158## ##STR00159## ##STR00160##
##STR00161## ##STR00162## ##STR00163## ##STR00164## ##STR00165##
##STR00166## ##STR00167## ##STR00168## ##STR00169## ##STR00170##
##STR00171## ##STR00172## ##STR00173## ##STR00174## ##STR00175##
##STR00176## ##STR00177## ##STR00178## ##STR00179## ##STR00180##
##STR00181## ##STR00182## ##STR00183## ##STR00184## ##STR00185##
##STR00186## ##STR00187## ##STR00188## ##STR00189## ##STR00190##
##STR00191## ##STR00192## ##STR00193## ##STR00194## ##STR00195##
##STR00196## ##STR00197## ##STR00198## ##STR00199## ##STR00200##
##STR00201## ##STR00202## ##STR00203## ##STR00204## ##STR00205##
##STR00206## ##STR00207## ##STR00208## ##STR00209## ##STR00210##
##STR00211## ##STR00212## ##STR00213## ##STR00214## ##STR00215##
##STR00216## ##STR00217## ##STR00218## ##STR00219## ##STR00220##
##STR00221## ##STR00222## ##STR00223## ##STR00224## ##STR00225##
##STR00226## ##STR00227## ##STR00228## ##STR00229## ##STR00230##
##STR00231## ##STR00232## ##STR00233## ##STR00234## ##STR00235##
##STR00236## ##STR00237## ##STR00238## ##STR00239## ##STR00240##
##STR00241## ##STR00242## ##STR00243## ##STR00244## ##STR00245##
##STR00246##
##STR00247## ##STR00248## ##STR00249## ##STR00250## ##STR00251##
##STR00252## ##STR00253## ##STR00254## ##STR00255## ##STR00256##
##STR00257## ##STR00258## ##STR00259## ##STR00260## ##STR00261##
##STR00262## ##STR00263## ##STR00264## ##STR00265## ##STR00266##
##STR00267## ##STR00268## ##STR00269## ##STR00270## ##STR00271##
##STR00272## ##STR00273## ##STR00274## ##STR00275## ##STR00276##
##STR00277## ##STR00278## ##STR00279## ##STR00280## ##STR00281##
##STR00282## ##STR00283## ##STR00284## ##STR00285## ##STR00286##
##STR00287## ##STR00288## ##STR00289## ##STR00290## ##STR00291##
##STR00292## ##STR00293## ##STR00294## ##STR00295## ##STR00296##
##STR00297## ##STR00298## ##STR00299## ##STR00300## ##STR00301##
##STR00302## ##STR00303## ##STR00304## ##STR00305## ##STR00306##
##STR00307## ##STR00308## ##STR00309## ##STR00310## ##STR00311##
##STR00312## ##STR00313## ##STR00314## ##STR00315## ##STR00316##
##STR00317## ##STR00318## ##STR00319## ##STR00320##
Preparation of the Substituted Heterocyclic Derivative
Compounds
The compounds used in the reactions described herein are made
according to organic synthesis techniques known to those skilled in
this art, starting from commercially available chemicals and/or
from compounds described in the chemical literature. "Commercially
available chemicals" are obtained from standard commercial sources
including Acros Organics (Pittsburgh, Pa.), Aldrich Chemical
(Milwaukee, Wis., including Sigma Chemical and Fluka), Apin
Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire,
U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.),
Chemservice Inc. (West Chester, Pa.), Crescent Chemical Co.
(Hauppauge, N.Y.), Eastman Organic Chemicals, Eastman Kodak Company
(Rochester, N.Y.), Fisher Scientific Co. (Pittsburgh, Pa.), Fisons
Chemicals (Leicestershire, UK), Frontier Scientific (Logan, Utah),
ICN Biomedicals, Inc. (Costa Mesa, Calif.), Key Organics (Cornwall,
U.K.), Lancaster Synthesis (Windham, N.H.), Maybridge Chemical Co.
Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, Utah), Pfaltz
& Bauer, Inc. (Waterbury, Conn.), Polyorganix (Houston, Tex.),
Pierce Chemical Co. (Rockford, Ill.), Riedel de Haen AG (Hanover,
Germany), Spectrum Quality Product, Inc. (New Brunswick, N.J.), TCI
America (Portland, Oreg.), Trans World Chemicals, Inc. (Rockville,
Md.), and Wako Chemicals USA, Inc. (Richmond, Va.).
Methods known to one of ordinary skill in the art are identified
through various reference books and databases. Suitable reference
books and treatise that detail the synthesis of reactants useful in
the preparation of compounds described herein, or provide
references to articles that describe the preparation, include for
example, "Synthetic Organic Chemistry", John Wiley & Sons,
Inc., New York; S. R. Sandler et al., "Organic Functional Group
Preparations," 2nd Ed., Academic Press, New York, 1983; H. O.
House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc.
Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry",
2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced
Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed.,
Wiley-Interscience, New York, 1992. Additional suitable reference
books and treatise that detail the synthesis of reactants useful in
the preparation of compounds described herein, or provide
references to articles that describe the preparation, include for
example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts,
Methods, Starting Materials", Second, Revised and Enlarged Edition
(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V.
"Organic Chemistry, An Intermediate Text" (1996) Oxford University
Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic
Transformations: A Guide to Functional Group Preparations" 2nd
Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced
Organic Chemistry: Reactions, Mechanisms, and Structure" 4th
Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera,
J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN:
3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of
Functional Groups" (1992) Interscience ISBN: 0-471-93022-9;
Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John
Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J. C.,
"Intermediate Organic Chemistry" 2nd Edition (1993)
Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic
Chemicals: Starting Materials and Intermediates: An Ullmann's
Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in
8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons,
in over 55 volumes; and "Chemistry of Functional Groups" John Wiley
& Sons, in 73 volumes.
Specific and analogous reactants may also be identified through the
indices of known chemicals prepared by the Chemical Abstract
Service of the American Chemical Society, which are available in
most public and university libraries, as well as through on-line
databases (the American Chemical Society, Washington, D.C., may be
contacted for more details). Chemicals that are known but not
commercially available in catalogs may be prepared by custom
chemical synthesis houses, where many of the standard chemical
supply houses (e.g., those listed above) provide custom synthesis
services. A reference for the preparation and selection of
pharmaceutical salts of the substituted heterocyclic derivative
compounds described herein is P. H. Stahl & C. G. Wermuth
"Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta,
Zurich, 2002.
The substituted heterocyclic derivative compounds are prepared by
the general synthetic routes described below in Schemes 1-2.
The substituted pyrrole derivative compounds are prepared by the
general synthetic route described below in Scheme 1.
Referring to Scheme 1, compound AE is obtained from N-alkylation of
compound AC with a variety of alkyl halides AD-X. Compound AG is
prepared from aryl halide compound AE using palladium-mediated aryl
cross coupling conditions with boronic acids AF--B(OH).sub.2.
Compound AI is prepared from aryl halide compound AG using
palladium-mediated aryl cross coupling conditions with boronic
acids AH--B(OH).sub.2. Hydrolysis of compound AI affords compound
AJ. Amide coupling is carried out with a variety of amines AKAK'-NH
and compound AJ to form compound AL.
##STR00321##
The substituted imidazole derivative compounds are prepared by the
general synthetic route described below in Scheme 2.
##STR00322##
Referring to Scheme 2, substituted aniline (BL-NH.sub.2) is first
treated with a base followed by reaction with an aromatic nitrile
(BK--CN) to form amidine intermediate BM. Compound BM is then
treated with .alpha.-bromo-oxobutanoate in presence of a base at
room temperature or under heating condition. After the first
alkylation intermediate is formed, treatment with an acid affects
the cyclization to give compound BO. Saponification followed by
HATU coupling with an amine to affords the final product BQ.
Pharmaceutical Compositions
In certain embodiments, the substituted heterocyclic derivative
compound as described herein is administered as a pure chemical. In
other embodiments, the substituted heterocyclic derivative compound
described herein is combined with a pharmaceutically suitable or
acceptable carrier (also referred to herein as a pharmaceutically
suitable (or acceptable) excipient, physiologically suitable (or
acceptable) excipient, or physiologically suitable (or acceptable)
carrier) selected on the basis of a chosen route of administration
and standard pharmaceutical practice as described, for example, in
Remington: The Science and Practice of Pharmacy (Gennaro, 21.sup.st
Ed. Mack Pub. Co., Easton, Pa. (2005)), the disclosure of which is
hereby incorporated herein by reference in its entirety.
Accordingly, provided herein is a pharmaceutical composition
comprising at least one substituted heterocyclic derivative
compound, or a stereoisomer, pharmaceutically acceptable salt,
hydrate, solvate, or N-oxide thereof, together with one or more
pharmaceutically acceptable carriers. The carrier(s) (or
excipient(s)) is acceptable or suitable if the carrier is
compatible with the other ingredients of the composition and not
deleterious to the recipient (i.e., the subject) of the
composition.
One embodiment provides a pharmaceutical composition comprising a
compound of Formula (I), or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable excipient.
In certain embodiments, the substituted heterocyclic derivative
compound as described by Formula (I) is substantially pure, in that
it contains less than about 5%, or less than about 1%, or less than
about 0.1%, of other organic small molecules, such as contaminating
intermediates or by-products that are created, for example, in one
or more of the steps of a synthesis method.
Suitable oral dosage forms include, for example, tablets, pills,
sachets, or capsules of hard or soft gelatin, methylcellulose or of
another suitable material easily dissolved in the digestive tract.
Suitable nontoxic solid carriers can be used which include, for
example, pharmaceutical grades of mannitol, lactose, starch,
magnesium stearate, sodium saccharin, talcum, cellulose, glucose,
sucrose, magnesium carbonate, and the like. (See, e.g., Remington:
The Science and Practice of Pharmacy (Gennaro, 21.sup.st Ed. Mack
Pub. Co., Easton, Pa. (2005)).
The dose of the composition comprising at least one substituted
heterocyclic derivative compound as described herein may differ,
depending upon the patient's (e.g., human) condition, that is,
stage of the disease, general health status, age, and other factors
that a person skilled in the medical art will use to determine
dose.
Pharmaceutical compositions may be administered in a manner
appropriate to the disease to be treated (or prevented) as
determined by persons skilled in the medical arts. An appropriate
dose and a suitable duration and frequency of administration will
be determined by such factors as the condition of the patient, the
type and severity of the patient's disease, the particular form of
the active ingredient, and the method of administration. In
general, an appropriate dose and treatment regimen provides the
composition(s) in an amount sufficient to provide therapeutic
and/or prophylactic benefit (e.g., an improved clinical outcome,
such as more frequent complete or partial remissions, or longer
disease-free and/or overall survival, or a lessening of symptom
severity. Optimal doses may generally be determined using
experimental models and/or clinical trials. The optimal dose may
depend upon the body mass, weight, or blood volume of the
patient.
Oral doses can typically range from about 1.0 mg to about 1000 mg,
one to four times, or more, per day.
Biology
Epigenetics is the study of heritable changes in gene expression
caused by mechanisms other than the underlying DNA sequence.
Molecular mechanisms that play a role in epigenetic regulation
include DNA methylation and chromatin/histone modifications.
The genomes of eukaryotic organisms are highly organized within the
nucleus of the cell. Tremendous compaction is required to package
the 3 billion nucleotides of the human genome into the nucleus of a
cell. Chromatin is the complex of DNA and protein that makes up
chromosomes. Histones are the major protein component of chromatin,
acting as spools around which DNA winds. Changes in chromatin
structure are affected by covalent modifications of histone
proteins and by non-histone binding proteins. Several classes of
enzymes are known which can modify histones at various sites.
There are a total of six classes of histones (HI, H2A, H2B, H3, H4,
and H5) organized into two groups: core histones (H2A, H2B, H3, and
H4) and linker histones (HI and H5). The basic unit of chromatin is
the nucleosome, which consists of about 147 base pairs of DNA
wrapped around the core histone octamer, consisting of two copies
each of the core histones H2A, H2B, H3, and H4.
Basic nucleosome units are then further organized and condensed by
the aggregation and folding of nucleosomes to form a highly
condensed chromatin structure. A range of different states of
condensation are possible, and the tightness of chromatin structure
varies during the cell cycle, being most compact during the process
of cell division.
Chromatin structure plays a critical role in regulating gene
transcription, which cannot occur efficiently from highly condensed
chromatin. The chromatin structure is controlled by a series of
post translational modifications to histone proteins, notably
histones H3 and H4, and most commonly within the histone tails
which extend beyond the core nucleosome structure. These
modifications acetylation, methylation, phosphorylation,
ribosylation sumoylation, ubiquitination, citrullination,
deimination, and biotinylation. The core of histones H2A and H3 can
also be modified. Histone modifications are integral to diverse
biological processes such as gene regulation, DNA repair, and
chromosome condensation.
Histone methylation is one of the most important chromatin marks;
these play important roles in transcriptional regulation,
DNA-damage response, heterochromatin formation and maintenance, and
X-chromosome inactivation. A recent discovery also revealed that
histone methylation affects the splicing outcome of pre-mRNA by
influencing the recruitment of splicing regulators. Histone
methylation includes mono-, di-, and tri-methylation of lysines,
and mono-, symmetric di-, and asymmetric di-methylation of
arginines. These modifications can be either an activating or
repressing mark, depending on the site and degree of
methylation.
Histone Demethylases
A "demethylase" or "protein demethylase," as referred to herein,
refers to an enzyme that removes at least one methyl group from
polypeptide. Demethylases comprise a JmjC domain, and can be a
methyl-lysine or methyl-arginine demethylase. Some demethylases act
on histones, e.g., act as a histone H3 or H4 demethylase. For
example, an H3 demethylase may demethylate one or more of H3K4,
H3K9, H3K27, H3K36 and/or H3K79. Alternately, an H4 demethylase may
demethylate histone H4K20. Demethylases are known which can
demethylate either a mono-, di- and/or a tri-methylated substrate.
Further, histone demethylases can act on a methylated core histone
substrate, a mononucleosome substrate, a dinucleosome substrate
and/or an oligonucleosome substrate, peptide substrate and/or
chromatin (e.g., in a cell-based assay).
The first lysine demethylase discovered was lysine specific
demethylase 1 (LSD1/KDM1), which demethylates both mono- and
di-methylated H3K4 or H3K9, using flavin as a cofactor. A second
class of Jumonji C (JmjC) domain containing histone demethylases
were predicted, and confirmed when a H3K36 demethylase was found
used a formaldehyde release assay, which was named JmjC domain
containing histone demethylase 1 (JHDM1/KDM2A).
More JmjC domain-containing proteins were subsequently identified
and they can be phylogenetically clustered into seven subfamilies:
JHDM1, JHDM2, JHDM3, JMJD2, JARID, PHF2/PHF8, UTX/UTY, and JmjC
domain only.
LSD-1
Lysine-specific demethylase 1 (LSD1) is a histone lysine
demethylase that specifically demethylates monomethylated and
dimethylated histone H3 at K4 and also demethylates dimethylated
histone H3 at K9. Although the main target of LSD1 appears to be
mono- and di-methylated histone lysines, specifically H3K4 and
H3K9, there is evidence in the literature that LSD 1 can
demethylate methylated lysines on non-histone proteins like p53,
E2F1, Dnmt1 and STAT3.
LSD 1 has a fair degree of structural similarity and amino acid
identity/homology to polyamine oxidases and monoamine oxidases, all
of which (i. e., MAO-A, MAO-B and LSD1) are flavin dependent amine
oxidases which catalyze the oxidation of nitrogen-hydrogen bonds
and/or nitrogen-carbon bonds. LSD1 also includes an N-terminal
SWRIM domain. There are two transcript variants of LSD1 produced by
alternative splicing.
Methods of Use
In some embodiments, the compounds disclosed herein are capable of
inhibiting LSD1 activity in a biological sample by contacting the
biological sample with a substituted heterocyclic compound as
disclosed herein. In some embodiments, a substituted heterocyclic
compound as disclosed herein is capable of modulating the level of
histone 4 lysine 3 methylation in the biological sample. In some
embodiments, a substituted heterocyclic compound as disclosed
herein is capable of modulating histone-3 lysine-9 methylation
levels in the biological sample.
In some embodiments, a substituted heterocyclic compound as
disclosed herein inhibits LSD1 activity to a greater extent than
MAO-A and/or MAO-B.
One embodiment provides a method of regulating gene transcription
in a cell comprising inhibiting lysine-specific demethylase 1
activity by exposing the lysine-specific demethylase 1 enzyme to a
compound of Formula (I).
Methods of Treatment
Disclosed herein are methods of modulating demethylation in a cell
or in a subject, either generally or with respect to one or more
specific target genes. Demethylation can be modulated to control a
variety of cellular functions, including without limitation:
differentiation; proliferation; apoptosis; tumorigenesis,
leukemogenesis or other oncogenic transformation events; hair loss;
or sexual differentiation.
One embodiment provides a method of treating cancer in a patient in
need thereof, comprising administering to the patient a compound of
Formula (I), or a pharmaceutically acceptable salt thereof.
In a further embodiment is the method for treating cancer in a
subject wherein the cancer is selected from prostate cancer, breast
cancer, bladder cancer, lung cancer or melanoma.
Other embodiments and uses will be apparent to one skilled in the
art in light of the present disclosures. The following examples are
provided merely as illustrative of various embodiments and shall
not be construed to limit the invention in any way.
EXAMPLES
I. Chemical Synthesis
Unless otherwise noted, reagents and solvents were used as received
from commercial suppliers. Anhydrous solvents and oven-dried
glassware were used for synthetic transformations sensitive to
moisture and/or oxygen. Yields were not optimized. Reaction times
are approximate and were not optimized. Column chromatography and
thin layer chromatography (TLC) were performed on silica gel unless
otherwise noted. Spectra are given in ppm (.delta.) and coupling
constants, J are reported in Hertz. For proton spectra the solvent
peak was used as the reference peak.
Preparation 1A: ethyl
4-bromo-1-methyl-5-p-tolyl-1H-pyrrole-2-carboxylate
##STR00323##
A mixture of ethyl 4,5-dibromo-1-methyl-1H-pyrrole-2-carboxylate
(3.7 g, 11.9 mmol), p-tolylboronic acid (1.62 g, 11.9 mmol),
Pd(PPh.sub.3).sub.4 (275 mg, 0.24 mmol) and 2M Na.sub.2CO.sub.3
(2.5 g, 23.8 mmol) in in toluene/ethanol (30/10 mL) was flushed
with nitrogen and stirred at 90.degree. C. for 3 h. Water was added
and the solution was extracted with EA (3.times.). The organics
were combined, washed with water, washed with brine, dried and
concentrated. The residue was purified by silica gel chromatography
(1:1, EA:PE) to give 530 mg (14%) of the title compound. .sup.1H
NMR (400 MHz, CDCl.sub.3): .delta. ppm 1.36 (t, J=7.2 Hz, 3H), 2.42
(s, 3H), 3.78 (s, 3H), 4.27-4.32 (m, 2H), 7.06 (s, 1H), 7.24-7.30
(m, 4H). [M+H] Calc'd for C.sub.15H.sub.16BrNO.sub.2, 322-324;
Found, 322-324.
Preparation 1B: ethyl
4-(4-cyanophenyl)-1-methyl-5-p-tolyl-1H-pyrrole-2-carboxylate
##STR00324##
A mixture of ethyl
4-bromo-1-methyl-5-p-tolyl-1H-pyrrole-2-carboxylate (530 mg, 1.65
mmol) was added 4-cyanophenylboronic acid (371 mg, 2.48 mmol),
Pd(PPh.sub.3).sub.4 (190 mg, 0.17 mmol) and 2M Na.sub.2CO.sub.3
(1.7 mL, 3.4 mmol) in DMF (5 mL) was flushed with nitrogen and
stirred at 90.degree. C. for 4 h. Water was added and the solution
was extracted with EA (3.times.). The organics were combined,
washed with water, washed with brine, dried and concentrated. The
residue was purified by silica gel chromatography (1:5, EA:PE) to
give 200 mg (35%) of the title compound. .sup.1H NMR (300 MHz,
CDCl.sub.3): .delta. ppm 1.39 (t, J=7.1 Hz, 3H), 2.43 (s, 3H), 3.75
(s, 3H), 4.30-4.37 (m, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.18-7.26 (m,
5H), 7.43 (d, J=8.4 Hz, 2H). [M+H] Calc'd for
C.sub.22H.sub.20N.sub.2O.sub.2, 345; Found, 345.
Preparation 1C:
4-(4-cyanophenyl)-1-methyl-5-p-tolyl-1H-pyrrole-2-carboxylic
acid
##STR00325##
2M NaOH solution (4 mL) was added to a solution of ethyl
4-(4-cyanophenyl)-1-methyl-5-p-tolyl-1H-pyrrole-2-carboxylate (200
mg, 0.58 mmol) in ethanol/THF (6/2 mL), and the mixture was stirred
at RT overnight. The solution was adjusted to PH=2-3 and extracted
with DCM (3.times.). The organics were combined, washed with water,
washed with brine, dried and concentrated to give 160 mg (87%) of
the title compound. [M-H] Calc'd for
C.sub.20H.sub.16N.sub.2O.sub.2, 315; Found, 315.
Preparation 1 D: (R)-tert-butyl
1-(3-(4-cyanophenyl)-1-methyl-2-p-tolyl-1H-pyrrole-5-carbonyl)piperidin-3-
-ylcarbamate
##STR00326##
To a mixture of
4-(4-cyanophenyl)-1-methyl-5-p-tolyl-1H-pyrrole-2-carboxylic acid
(160 mg, 0.5 mmol) in DCM (10 mL) was added EDCI (144 mg, 0.55
mmol), HOBT (68 mg, 0.75 mmol), (R)-tert-butyl
piperidin-3-ylcarbamate (110 mg, 0.55 mmol) and DIEA (129 mg, 2.0
mmol), and the solution was stirred at RT overnight. Water was
added and the solution was extracted with DCM (3.times.). The
organics were combined, washed with water, washed with brine, dried
and concentrated. The residue was purified by silica gel
chromatography (1:5, EA:PE) to give 130 mg (53%) of the title
compound. [M+H] Calc'd for C.sub.30H.sub.34N.sub.4O.sub.3, 499;
Found, 499.
Example 1:
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-methyl-2-p-tolyl-1H--
pyrrol-3-yl]-benzonitrile
##STR00327##
To a solution of (R)-tert-butyl
1-(3-(4-cyanophenyl)-1-methyl-2-p-tolyl-1H-pyrrole-5-carbonyl)piperidin-3-
-ylcarbamate (130 mg, 0.26 mmol) in EA (1 mL) was added a 4N HCl
solution in EA (2 mL), and the mixture was stirred at RT for 1 h.
The solvent was concentrated in vacuo to give 108 mg (96%) of the
title compound as the HCl salt. .sup.1H NMR (CD.sub.3OD, 400 MHz):
.delta. ppm 1.67-1.71 (m, 2H), 1.87-1.90 (m, 1H), 2.17-2.19 (m,
1H), 2.39 (s, 3H), 3.30-3.37 (m, 3H), 3.49 (s, 3H), 4.21 (d, J=13.6
Hz, 1H), 4.46-4.49 (m, 1H), 6.79 (s, 1H), 7.14 (d, J=7.6 Hz, 2H),
7.26-7.29 (m, 4H), 7.46 (d, J=8.0 Hz, 2H). [M+H] Calc'd for
C.sub.25H.sub.26N.sub.4O, 399; Found, 399.
Example 2:
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-2-(4-methoxy-phenyl)-1-
-methyl-1H-pyrrol-3-yl]-2-fluoro-benzonitrile
##STR00328##
The title compound was prepared as the HCl salt in 7% overall yield
according to the general procedure for the preparation of Example
1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 1.70-1.73 (m,
2H), 1.88-1.91 (m, 1H), 2.20-2.22 (m, 1H), 3.35-3.37 (m, 3H), 3.50
(s, 3H), 3.85 (s, 3H), 4.22 (d, J=11.6 Hz, 1H), 4.47-4.50 (m, 1H),
6.84 (s, 1H), 7.05-7.10 (m, 4H), 7.21 (d, J=7.6 Hz, 2H), 7.47 (t,
J=7.4 Hz, 1H). [M+H] Calc'd for C.sub.25H.sub.25N.sub.4O.sub.2,
433; Found, 433.
Example 3:
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-(2-hydroxy-ethyl)-2--
p-tolyl-1H-pyrrol-3-yl]-benzonitrile
##STR00329##
The title compound was prepared as the HCl salt in 14% overall
yield according to the general procedure for the preparation of
Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 1.71-1.74
(m, 2H), 1.86-1.87 (m, 1H), 2.17-2.20 (m, 1H), 2.41 (s, 3H),
3.36-3.42 (m, 5H), 4.17-4.49 (m, 1H), 3.85 (s, 3H), 6.79 (s, 1H),
7.18 (d, J=8.0 Hz, 2H), 7.25-7.30 (m, 4H), 7.45 (t, J=8.8 Hz, 2H).
[M+H] Calc'd for C.sub.26H.sub.28N.sub.4O.sub.2, 429; Found,
429.
Example 4:
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-(2-hydroxy-ethyl)-2--
p-tolyl-1H-pyrrol-3-yl]-2-fluoro-benzonitrile
##STR00330##
The title compound was prepared as the HCl salt in 13% overall
yield according to the general procedure for the preparation of
Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 1.70-1.73
(m, 2H), 1.83-1.86 (m, 1H), 2.15-2.20 (m, 1H), 2.40 (s, 3H),
3.31-3.42 (m, 5H), 4.14-4.23 (m, 3H), 4.45-4.48 (m, 1H), 6.82 (s,
1H), 6.99-7.07 (m, 2H), 7.19 (d, J=7.6 Hz, 2H), 7.32 (d, J=8.0 Hz,
2H), 7.45 (t, J=7.6 Hz, 1H). [M+H] Calc'd for
C.sub.26H.sub.27FN.sub.4O.sub.2, 447; Found, 447.
Example 5:
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-methyl-2-(6-methyl-p-
yridin-3-yl)-1H-pyrrol-3-yl]-benzonitrile
##STR00331##
The title compound was prepared as the HCl salt in 21% overall
yield according to the general procedure for the preparation of
Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 1.67-1.76
(m, 2H), 1.89-1.92 (m, 1H), 2.19-2.21 (m, 1H), 2.84 (s, 3H),
3.32-3.39 (m, 3H), 3.63 (s, 3H), 4.16-4.20 (m, 1H), 4.48-4.51 (m,
1H), 6.81 (s, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H),
7.98 (d, J=8.4 Hz, 1H), 8.40-8.43 (m, 1H), 8.74 (d, J=2.0 Hz, 1H).
[M+H] Calc'd for C.sub.24H.sub.25N.sub.5O, 400; Found, 400.
Example 6:
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-methyl-2-pyridin-4-y-
l-1H-pyrrol-3-yl]-benzonitrile
##STR00332##
The title compound was prepared as the HCl salt in 25% overall
yield according to the general procedure for the preparation of
Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 1.67-1.73
(m, 2H), 1.88-1.92 (m, 1H), 2.18-2.20 (m, 1H), 3.30-3.39 (m, 3H),
3.73 (s, 3H), 4.13-4.16 (m, 1H), 4.45-4.49 (m, 1H), 6.77 (s, 1H),
7.38 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H), 7.94 (d, J=8.6 Hz,
2H), 8.77 (d, J=6.8 Hz, 2H). [M+H] Calc'd for
C.sub.23H.sub.23N.sub.5O, 386; Found, 386.
Example 7:
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-(2-hydroxy-ethyl)-2--
(4-methoxy-phenyl)-1H-pyrrol-3-yl]-benzonitrile
##STR00333##
The title compound was prepared as the HCl salt in 16% overall
yield according to the general procedure for the preparation of
Example 1. .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. ppm 1.67-1.73
(m, 2H), 1.82-1.86 (m, 1H), 2.13-2.15 (m, 1H), 3.32-3.42 (m, 5H),
3.81 (s, 3H), 4.14-4.25 (m, 3H), 4.43-4.49 (m, 1H), 6.77 (s, 1H),
7.00 (d, J=8.7 Hz, 2H), 7.17-7.26 (m, 4H), 7.44 (d, J=8.7 Hz, 2H).
[M+H] Calc'd for C.sub.26H.sub.28N.sub.4O.sub.3, 445; Found,
445.
Example 8:
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-(2-hydroxy-ethyl)-2--
(4-methoxy-phenyl)-1H-pyrrol-3-yl]-2-fluoro-benzonitrile
##STR00334##
The title compound was prepared as the HCl salt in 15% overall
yield according to the general procedure for the preparation of
Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 1.70-1.76
(m, 2H), 1.86-1.89 (m, 1H), 2.01-2.06 (m, 1H), 3.36-3.48 (m, 5H),
3.87 (s, 3H), 4.18-4.26 (m, 3H), 4.86-4.51 (m, 1H), 6.84 (s, 1H),
7.04-7.10 (m, 4H), 7.24 (d, J=8.8 Hz, 2H), 7.46-7.50 (m, 1H). [M+H]
Calc'd for C.sub.26H.sub.27FN.sub.4O.sub.3, 463; Found, 463.
Example 9:
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-(3-hydroxy-propyl)-2-
-(4-methoxy-phenyl)-1H-pyrrol-3-yl]-2-fluoro-benzonitrile
##STR00335##
The title compound was prepared as the HCl salt in 13% overall
yield according to the general procedure for the preparation of
Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 1.54-1.61
(m, 2H), 1.73-1.78 (m, 2H), 1.87-1.92 (m, 1H), 2.18-2.22 (m, 1H),
2.42 (s, 3H), 3.24-3.49 (m, 5H), 4.11-4.21 (m, 3H), 4.38-4.41 (m,
1H), 6.85 (s, 1H), 7.01-7.08 (m, 2H), 7.20 (d, J=8.0 Hz, 2H), 7.33
(d, J=8.0 Hz, 2H), 7.44-7.48 (m, 1H). [M+H] Calc'd for
C.sub.27H.sub.29FN.sub.4O.sub.2, 461; Found, 461.
Example 10:
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-methyl-2-(1-methyl-1H-benzoimi-
dazol-5-yl)-1H-pyrrol-3-yl]-2-fluoro-benzonitrile
##STR00336##
The title compound was prepared as the HCl salt in 21% overall
yield according to the general procedure for the preparation of
Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 1.69-1.77
(m, 2H), 1.90-1.96 (m, 1H), 2.00-2.22 (m, 1H), 3.33-3.42 (m, 3H),
3.53 (s, 3H), 4.17-4.24 (m, 4H), 4.50-4.53 (m, 1H), 6.87 (s, 1H),
7.04-7.07 (m, 2H), 7.43-7.47 (m, 1H), 7.61-7.63 (m, 1H), 7.84 (s,
1H), 8.06 (d, J=8.4 Hz, 1H), 9.50 (s, 1H). [M+H] Calc'd for
C.sub.26H.sub.25FN.sub.6O, 457; Found, 457.
Preparation 11A:
4-Cyano-N-(4-methylphenyl)benzenecarboximidamide
##STR00337##
To a suspension of NaH (60% in mineral oil) (2.34 g, 58.5 mmol,
60%, 1.5 equiv) in DMSO (80 mL) at 0.degree. C. was added
p-toluidine (4.6 g, 43.0 mmol, 1.1 equiv) and 1,4-dicyanobenzene
(5.0 g, 39.0 mmol). The mixture was kept at 0.degree. C. for 15 min
and then stirred at rt for 1 h. Ice-water (500 mL) was added while
maintaining vigorous stirring. The precipitate was filtered, washed
with water and dried to give 6.11 g of the desired product as a
yellow solid (67%). [M+H] Calc'd for C.sub.15H.sub.13N.sub.3, 236;
Found, 236.
Preparation 11B: Ethyl
2-(4-cyanophenyl)-5-methyl-1-(4-methylphenyl)imidazole-4-carboxylate
##STR00338##
To a mixture of 4-cyano-N-(4-methylphenyl)benzenecarboximidamide
(470 mg, 2 mmol) in EtOH (10 mL) was added
ethyl-3-bromo-2-oxobutanoate (500 mg, 2.4 mmol), followed by sodium
bicarbonate (252 mg, 3 mmol). The reaction mixture was heated at
90.degree. C. overnight. The solid was filtered and filtrate was
concentrated to a residue, which was dissolved in acetic acid (5
mL) and heated to 120.degree. C. for 3 h. The reaction mixture was
then concentrated and purified by flash column (EtOAc/Hexane) to
give the title compound as an orange solid (270 mg, 40%). .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 1.31 (3H, t, J=7.4 Hz), 2.29
(3H, s), 2.39 (3H, s), 4.29 (2H, q, J=7.1 Hz), 7.29 (2H, d, J=8.2
Hz), 7.37 (2H, d, J=8.2 Hz), 7.45 (2H, d, J=8.3 Hz), 7.75 (2H, d,
J=8.4 Hz). [M+H] Calc'd for C.sub.21H.sub.19N.sub.3O.sub.2, 346;
Found, 346.
Preparation 11C: 2-(4-Cyanophenyl)-5-methyl-1-(4-methylphenyl)
imidazole-4-carboxylic acid
##STR00339##
A solution of ethyl
2-(4-cyanophenyl)-5-methyl-1-(4-methylphenyl)imidazole-4-carboxylate
(240 mg, 0.8 mmol) in a mixture of THF (2 mL) and EtOH (6 mL) was
treated with 2M NaOH (2 mL). The reaction mixture was stirred at rt
overnight. It was then acidified by 1N HCl, followed by extraction
with EtOAc. Organic layer was separated, dried and concentrated to
give the title compound as an orange solid (120 mg, 48%). [M+H]
Calc'd for C.sub.19H5N.sub.3O.sub.2, 318; Found, 318.
Example 11:
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5-methyl-1-(4-methylphenyl)imida-
zol-2-yl]benzonitrile
##STR00340##
To a mixture of 2-(4-cyanophenyl)-5-methyl-1-(4-methylphenyl)
imidazole-4-carboxylic acid (120 mg, 0.38 mmol),
(R)-3-boc-aminopiperidine (114 mg, 0.57 mmol) and DIEA (126 uL,
0.57 mmol) in DMF was added HATU (217 mg, 0.57 mmol). The reaction
mixture was stirred at rt for 2 h. It was then separated between
water and EtOAc. The organic extract was dried and concentrated to
a residue, which was dissolved in CH.sub.2Cl.sub.2 (5 mL) and
treated with TFA (2 mL). After 2 h, the reaction mixture was
concentrated and purified by prep-HPLC to afford the title compound
as the formic acid salt (20 mg, 16%) as a white solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 1.35-1.52 (2H, m), 1.74 (1H, m),
1.95 (1H, m), 2.16 (3H, s), 2.40 (3H, s), 2.89 (1H, m), 3.20 (2H,
m), 4.57 (2H. m), 7.28 (2H, d, J=7.8 Hz), 7.37 (2H, d, J=8.2 Hz),
7.45 (2H, m), 7.75 (2H, d, J=8.4 Hz), 8.28 (1H, s). [M+H] Calc'd
for C.sub.24H.sub.25N.sub.5O, 400; Found, 400.
Preparation 12A:
4-Bromo-3-fluoro-N-(4-methoxyphenyl)benzenecarboximidamide
##STR00341##
To 20 mL of EtMgBr (1M in THF) in 10 mL of THF, under nitrogen, was
carefully added p-anisidine (1.23 g, 10 mmol). After 30 minutes of
stirring at rt, 4-bromo-3-fluorobenzene nitrile (2.2 g, 11 mmol) in
5 mL THF was added dropwise. The mixture was stirred at rt for 20
h. Ice-water (10 mL) was carefully added while maintaining vigorous
stirring. The reaction mixture was separated between water and
EtOAc. Organic extract was dried and concentrated to a residue
which was purified by ISCO flash column (EtOAc/Hexane). Fractions
collected, concentrated and triturated with acetone and EtOAc to
give 1.5 g of the desired product as a reddish solid (46%). [M+H]
Calc'd for C.sub.14H.sub.12BrFN.sub.2O, 324; Found, 324.
Preparation 12B: Ethyl
2-(4-bromo-3-fluorophenyl)-5-methyl-1-(4-methoxyphenyl)imidazole-4-carbox-
ylate
##STR00342##
The title compound was prepared in 97% yield according to the
procedure of Preparation 11B, except the product was formed in one
pot without treatment with acid. [M+H] Calc'd for
C.sub.20H.sub.18BrFN.sub.2O.sub.3, 434; Found, 434.
Preparation 12C:
2-(4-Bromo-3-fluorophenyl)-5-methyl-1-(4-methoxyphenyl)imidazole-4-carbox-
ylic acid
##STR00343##
The title compound was prepared in 88% yield according to the
procedure of Preparation 11C. [M+H] Calc'd for
C.sub.18H.sub.14BrFN.sub.2O.sub.3, 406; Found, 406.
Preparation 12D:
N-[(3R)-1-[2-(4-bromo-3-fluorophenyl)-1-(4-methoxyphenyl)-5-methylimidazo-
le-4-carbonyl]piperidin-3-yl]carbamate
##STR00344##
To a mixture of
2-(4-bromo-3-fluorophenyl)-5-methyl-1-(4-methoxyphenyl)imidazole-4-carbox-
ylic acid (405 mg, 1 mmol), (R)-3-boc-aminopiperidine (300 mg, 1.5
mmol) and DIEA (331 .mu.L, 2 mmol) in DMF was added HATU (570 mg,
1.5 mmol). The reaction mixture was stirred at rt for 2 h. It was
then separated between water and EtOAc. The organic extract was
dried and concentrated to a residue, which was purified by ISCO
flash column (EtOAc/Hexane) to afford the title compound (460 mg,
78%). [M+H] Calc'd for C.sub.28H.sub.32BrFN.sub.4O.sub.4, 588;
Found, 588.
Example 12:
4-[4-[(3R)-3-aminopiperidine-1-carbonyl]-1-(4-methoxyphenyl)-5-methylimid-
azol-2-yl]-2-fluorobenzonitrile
##STR00345##
In a microwave vessel, was added
N-[(3R)-1-[2-(4-bromo-3-fluorophenyl)-1-(4-methoxyphenyl)-5-methylimidazo-
le-4-carbonyl]piperidin-3-yl]carbamate (400 mg, 0.68 mmol), zinc
cyanide (400 mg, 3.4 mmol) and Pd(PPh.sub.3).sub.4 (92 mg, 0.08
mmol) in 5 mL DMF. The reaction mixture was heated at 120.degree.
C. for 1 h in a microwave oven. It was then purified by ISCO flash
column (EtOAc/Hexane). The fractions were concentrated to a
residue, which was dissolved in CH.sub.2Cl.sub.2 (5 mL) and treated
with TFA (2 mL). After 2 h, the reaction mixture was concentrated
and purified by prep-HPLC to afford the title compound as the
formic acid salt (40 mg, 15%) as a light yellow solid. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 1.44 (2H, m), 1.75 (1H, m), 1.97
(1H, m), 2.15 (3H, s), 2.73 (2H, s), 2.89 (2H, m), 3.84 (3H, s),
4.56 (1H, m), 7.12 (2H, d, J=8.7 Hz), 7.21 (1H, d, J=8.2 Hz), 7.36
(2H, d, J=8.2 Hz), 7.84 (1H, t, J=7.7 Hz), 7.95 (1H, s), 8.30 (1H,
br s). [M+H] Calc'd for C.sub.24H.sub.24FN.sub.5O.sub.2, 434;
Found, 434.
Example 13:
4-[4-[(3R)-3-aminopyrrolidine-1-carbonyl]-1-(4-methoxyphenyl)-5-methylimi-
dazol-2-yl]-2-fluorobenzonitrile
##STR00346##
The title compound was prepared as the formic acid salt in 7% yield
according to the general procedure for the preparation of Example
12 starting from
2-(4-bromo-3-fluorophenyl)-5-methyl-1-(4-methoxyphenyl)imidazole-4-carbox-
ylic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.78 (1H,
m), 2.03 (1H, m), 2.19 (3H, s), 3.30 (1H, m), 3.60 (2H, m), 3.78
(1H, m), 3.85 (3H, s), 4.14 (2H, m), 7.13 (2H, d, J=8.8 Hz), 7.22
(1H, t, J=7.8 Hz), 7.33-7.38 (3H, m), 7.85 (1H, m), 8.28 (1H, br
s). [M+H] Calc'd for C.sub.23H.sub.22FN.sub.5O.sub.2, 420; Found,
420.
Example 14:
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-1-(4-methoxyphenyl)-5-methylimi-
dazol-2-yl]-2-fluorobenzonitrile
##STR00347##
The title compound was prepared as the formic acid salt in 10%
yield according to the general procedure for the preparation of
Example 12 starting from
2-(4-bromo-3-fluorophenyl)-5-methyl-1-(4-methoxyphenyl)imidazole-4-carbox-
ylic acid. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.78 (1H,
m), 2.03 (1H, m), 2.19 (3H, s), 3.30 (1H, m), 3.60 (2H, m), 3.78
(1H, m), 3.85 (3H, s), 4.14 (2H, m), 7.13 (2H, d, J=8.8 Hz), 7.22
(1H, t, J=7.8 Hz), 7.33-7.38 (3H, m), 7.85 (1H, m), 8.28 (1H, br
s). [M+H] Calc'd for C.sub.23H.sub.22FN.sub.5O.sub.2, 420; Found,
420.
Example 15:
4-[4-[(3R)-3-aminopiperidine-1-carbonyl]-1-(6-methoxypyridin-3-yl)-5-meth-
ylimidazol-2-yl]-2-fluorobenzonitrile
##STR00348##
The title compound was prepared as the formic acid salt in 22%
overall yield according to the general procedure for the
preparation of Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.58 (2H, m), 1.81 (1H, m), 2.06 (1H, m), 2.20 (3H, s),
2.98 (2H, m), 3.21 (2H, m), 3.95 (3H, s), 4.51 (1H, m), 7.05 (1H,
d, J=8.8 Hz), 7.19 (1H, d, J=7.7 Hz), 7.88 (2H, m), 7.98 (2H, m),
8.26 (1H, br s). [M+H] Calc'd for C.sub.23H.sub.23FN.sub.6O.sub.2,
435; Found, 435.
Example 16:
4-[4-[(3R)-3-aminopiperidine-1-carbonyl]-1-(3-fluoro-4-methoxyphenyl)-5-m-
ethylimidazol-2-yl]-2-fluorobenzonitrile
##STR00349##
The title compound was prepared as the formic acid salt in 15%
overall yield according to the general procedure for the
preparation of Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.58 (2H, m), 1.81 (1H, m), 2.04 (1H, m), 2.19 (3H, s),
2.73 (2H, s), 3.18-3.31 (2H, m), 3.93 (3H, s), 4.52 (1H, m), 7.19
(2H, m), 7.37 (2H, d, J=9.0 Hz), 7.54 (1H, m), 7.86 (1H, t, J=8.0
Hz), 8.00 (2H, br s). [M+H] Calc'd for
C.sub.24H.sub.23F.sub.2N.sub.5O.sub.2, 452; Found, 452.
Example 17:
4-[4-[(3S)-3-aminopiperidine-1-carbonyl]-1-(3-fluoro-4-methoxyphenyl)-5-m-
ethylimidazol-2-yl]-2-fluorobenzonitrile
##STR00350##
The title compound was prepared as the formic acid salt in 6%
overall yield according to the general procedure for the
preparation of Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.42 (2H, m), 1.78 (1H, m), 1.98 (2H, m), 2.16 (3H, s),
2.90 (1H, m), 3.15 (1H, m), 3.92 (3H, s), 4.54 (1H, m), 7.19 (1H,
d, J=8.1 Hz), 7.21 (1H, m), 7.34 (1H, t, J=8.8 Hz), 7.56 (1H, d,
J=10.4 Hz), 7.86 (1H, t, J=7.3 Hz), 8.28 (1H, br s). [M+H] Calc'd
for C.sub.24H.sub.23F.sub.2N.sub.5O.sub.2, 452; Found, 452.
Example 18:
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-1-(3-fluoro-4-methoxyphenyl)-5--
methylimidazol-2-yl]-2-fluorobenzonitrile
##STR00351##
The title compound was prepared as the formic acid salt in 5%
overall yield according to the general procedure for the
preparation of Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.71 (1H, m), 2.04 (2H, m), 2.25 (3H, s), 3.49 (1H, m),
3.76 (1H, m), 3.92 (3H, s), 4.16 (1H, m), 7.16 (1H, d, J=8.4 Hz),
7.25 (1H, m), 7.31 (1H, m), 7.39 (1H, t, J=7.7 Hz), 7.55 (1H, d,
J=11.5 Hz), 7.86 (1H, m), 8.26 (1H, s). [M+H] Calc'd for
C.sub.23H.sub.21F.sub.2N.sub.5O.sub.2, 438; Found, 438.
Example 19:
4-[4-[(3R)-3-aminopiperidine-1-carbonyl]-1-(3-fluoro-4-methoxyphenyl)imid-
azol-2-yl]-2-fluorobenzonitrile
##STR00352##
The title compound was prepared as the formic acid salt in 15%
overall yield according to the general procedure for the
preparation of Example 12 using ethyl bromopyruvate. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 1.38 (2H, m), 1.75 (2H, m), 1.93
(2H, m), 2.86 (2H, m), 3.90 (3H, s), 4.69 (1H, m), 7.19-7.31 (3H,
m), 7.52 (2H, dd, J=11.5 and 2.4 Hz), 7.90 (1H, t, J=7.9 Hz), 7.97
(1H, s), 8.24 (1H, s). [M+H] Calc'd for
C.sub.23H.sub.21F.sub.2N.sub.5O.sub.2, 438; Found, 438.
Example 20:
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-1-(3-fluoro-4-methoxyphenyl)imi-
dazol-2-yl]-2-fluorobenzonitrile
##STR00353##
The title compound was prepared as the formic acid salt in 8%
overall yield according to the general procedure for the
preparation of Example 12 using ethyl bromopyruvate. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 1.71-1.84 (1H, m), 1.99-2.08 (1H,
m), 3.37 (2H, m), 3.50 (1H, m), 3.71 (2H, m), 3.91 (3H, s),
4.06-4.18 (1H, m), 7.19-7.31 (3H, m), 7.54 (2H, dd, J=11.5 Hz),
7.93 (1H, m), 8.02 (1H, s), 8.25 (1H, s). [M+H] Calc'd for
C.sub.22H.sub.19F.sub.2N.sub.5O.sub.2, 424; Found, 424.
Example 21:
4-[4-[(3R)-3-aminopiperidine-1-carbonyl]-5-methyl-1-(2-methylindazol-5-yl-
)imidazol-2-yl]-2-fluorobenzonitrile
##STR00354##
The title compound was prepared as the formic acid salt in 6%
overall yield according to the general procedure for the
preparation of Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.45 (2H, m), 1.75 (1H, m), 1.97 (1H, m), 2.17 (3H, s),
2.93 (2H, m), 3.20 (1H, m), 4.16 (1H, m), 4.23 (3H, s), 4.46-4.62
(1H, m), 7.19 (2H, d, J=8.2 Hz), 7.39 (1H, m), 7.76-7.86 (2H, m),
8.27 (1H, s), 8.49 (1H, s). [M+H] Calc'd for
C.sub.25H.sub.24FN.sub.7O, 458; Found, 458.
Example 22:
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-5-methyl-1-(2-methylindazol-5-y-
l)imidazol-2-yl]-2-fluorobenzonitrile
##STR00355##
The title compound was prepared as the formic acid salt in 7%
overall yield according to the general procedure for the
preparation of Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.92 (1H, m), 2.05 (1H, m), 2.16 (1H, m), 2.21 (4H, s &
m), 3.70 (1H, m), 3.75 (1H, m), 3.81 (1H, m), 4.29 (3H, s),
7.11-7.21 (2H, m), 7.41 (1H, t, J=9.7 Hz), 7.74-7.95 (4H, m), 8.48
(1H, s). [M+H] Calc'd for C.sub.24H.sub.22FN.sub.7O, 444; Found,
444.
Example 23:
4-[4-[(3R)-3-aminopiperidine-1-carbonyl]-5-methyl-1-(1-methylindazol-5-yl-
)imidazol-2-yl]-2-fluorobenzonitrile
##STR00356##
The title compound was prepared as the formic acid salt in 4%
overall yield according to the general procedure for the
preparation of Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.46 (2H, m), 1.77 (1H, m), 1.98 (1H, m), 2.15 (3H, s),
2.97 (2H, m), 3.29 (2H, m), 4.13 (3H, s), 4.59 (1H, m), 7.14 (1H,
d, J=8.2 Hz), 7.42 (2H, m), 7.77 (1H, t, J=7.6 Hz), 7.86-7.91 (2H,
m), 8.17 (1H, s), 8.27 (1H, s). [M+H] Calc'd for
C.sub.25H.sub.24FN.sub.7O, 458; Found, 458.
Example 24:
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-5-methyl-1-(1-methylindazol-5-y-
l)imidazol-2-yl]-2-fluorobenzonitrile
##STR00357##
The title compound was prepared as the formic acid salt in 2%
overall yield according to the general procedure for the
preparation of Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.71-1.84 (1H, m), 2.00-2.09 (1H, m), 2.33 (3H, s), 3.53
(1H, m), 3.66 (2H, m), 3.84 (1H, m), 4.16 (4H, s & m), 7.14
(1H, t, J=9.7 Hz), 7.36-7.42 (2H, m), 7.76 (1H, m), 7.87 (1H, d,
J=8.6 Hz), 7.90 (1H, s), 8.17 (1H, s), 8.24 (1H, s). [M+H] Calc'd
for C.sub.24H.sub.22FN.sub.7O, 444; Found, 444.
Example 25:
4-[4-[(3R)-3-aminopiperidine-1-carbonyl]-1-(2-methylindazol-5-yl)imidazol-
-2-yl]-2-fluorobenzonitrile
##STR00358##
The title compound was prepared as the formic acid salt in 4%
overall yield according to the general procedure for the
preparation of Example 12 using ethyl bromopyruvate. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 1.49 (2H, m), 1.78 (1H, m), 1.99
(1H, m), 3.01 (1H, m), 3.19 (1H, m), 4.22 (3H, s), 4.42-4.96 (2H,
m), 7.11 (1H, dd, J=9.0 and 2.0 Hz), 7.24 (1H, dd, J=8.2 and 1.4
Hz), 7.51 (1H, m), 7.73 (1H, d, J=9 Hz), 7.82 (1H, t, J=7.3 Hz),
7.87 (1H, d, J=1.6 Hz), 8.02 (1H, s), 8.25 (1H, br s), 8.48 (1H,
s). [M+H] Calc'd for C.sub.24H.sub.22FN.sub.7O, 444; Found,
444.
Example 26:
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-1-(2-methylindazol-5-yl)imidazo-
l-2-yl]-2-fluorobenzonitrile
##STR00359##
The title compound was prepared as the formic acid salt in 2%
overall yield according to the general procedure for the
preparation of Example 12 using ethyl bromopyruvate. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 1.68-1.85 (1H, m), 2.01-2.13 (1H,
m), 3.30-3.41 (2H, m), 3.51-3.86 (3H, m), 3.89 (1H, m), 4.20 (4H, s
& m), 7.18 (1H, dd, J=9.1 and 2.1 Hz), 7.25 (1H, m), 7.46 (1H,
dd, J=10.7 and 1.4 Hz), 7.73 (1H, d, J=9.0 Hz), 7.81 (1H, m), 7.87
(1H, d, J=1.6 Hz), 8.04 (1H, s), 8.25 (1H, br s), 8.48 (1H, s).
[M+H] Calc'd for C.sub.23H.sub.20FN.sub.7O, 430; Found, 430.
Example 27:
4-[4-[(3R)-3-aminopiperidine-1-carbonyl]-1-(1-methylindazol-5-yl)imidazol-
-2-yl]-2-fluorobenzonitrile
##STR00360##
The title compound was prepared as the formic acid salt in 2%
overall yield according to the general procedure for the
preparation of Example 12 using ethyl bromopyruvate. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 1.59 (2H, m), 1.81 (1H, m), 2.03
(1H, m), 3.20 (1H, m), 4.11 (3H, s), 7.17 (1H, d, J=8.2 Hz), 7.37
(1H, d, J=9.8 Hz), 7.53 (1H, br s), 7.76-7.85 (3H, t & m, J=8.6
Hz), 7.98 (1H, s), 8.09 (1H, s), 8.16 (1H, s). [M+H] Calc'd for
C.sub.24H.sub.22FN.sub.7O, 444; Found, 444.
Example 28:
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-1-(1-methylindazol-5-yl)imidazo-
l-2-yl]-2-fluorobenzonitrile
##STR00361##
The title compound was prepared as the formic acid salt in 4%
overall yield according to the general procedure for the
preparation of Example 12 using ethyl bromopyruvate. .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 1.80-1.94 (1H, m), 2.07-2.19 (1H,
m), 3.32-3.46 (2H, m), 3.54-3.82 (3H, m), 4.03 (1H, m), 4.21 (4H, s
& m), 7.19 (1H, t, J=7.3 Hz), 7.39 (1H, dd, J=8.9 and 2.0 Hz),
7.47 (1H, d, J=10.6 Hz), 7.80 (1H, d, J=8.9 Hz), 7.86 (1H, m), 7.91
(1H, d, J=1.8 Hz), 8.07 (1H, s), 8.16 (1H, s), 8.27 (1H, s). [M+H]
Calc'd for C.sub.23H.sub.20FN.sub.7O, 430; Found, 430.
Example 29:
4-{5-[((3R)-3-aminopiperidyl)carbonyl]-1-methyl-2-(2-methyl(2H-indazol-5--
yl))pyrrol-3-yl}-2-fluorobenzenecarbonitrile
##STR00362##
The title compound was prepared as the HCl salt in 24% overall
yield according to the general procedure for the preparation of
Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD): .quadrature. ppm
1.76-1.80 (m, 2H), 1.95-1.96 (m, 1H), 2.23-2.25 (m, 1H), 3.32-3.46
(m, 3H), 3.58 (s, 3H), 4.30 (s, 3H), 4.26-4.33 (m, 1H), 4.55 (d,
J=10.0 Hz 1H), 6.91 (s, 1H), 7.10-7.14 (m, 2H), 7.29 (dd, J=8.8 Hz,
1.6 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.77-7.80 (m, 2H), 8.41 (s,
1H). [M+H] Calc'd for C.sub.26H.sub.25FN.sub.6O, 457; Found,
457.
Example 30:
N-((3R)pyrrolidin-3-yl)[4-(4-cyano-3-fluorophenyl)-1-methyl-5-(2-methyl(2-
H-indazol-5-yl))pyrrol-2-yl]carboxamide
##STR00363##
The title compound was prepared as the HCl salt in 18% overall
yield according to the general procedure for the preparation of
Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD): .quadrature. ppm
2.20-2.25 (m, 1H), 2.40-2.46 (m, 1H), 3.38-3.44 (m, 2H), 3.56-3.63
(m, 2H), 3.73 (s, 3H), 4.32 (s, 3H), 4.58-4.62 (m, 1H), 7.02 (dd,
J=1.6, 11.2 Hz, 1H), 7.09 (dd, J=1.6, 8.0 Hz, 1H), 7.30-7.33 (m,
2H), 7.46 (t, J=8.0 Hz, 1H)), 7.77-7.79 (m, 2H), 8.46 (s, 1H).
[M+H] Calc'd for C.sub.25H.sub.23FN.sub.6O, 443; Found, 443.
Example 31:
N-(2-aminoethyl)[4-(4-cyano-3-fluorophenyl)-1-methyl-5-(2-methyl(2H-indaz-
ol-5-yl))pyrrol-2-yl]-N-methylcarboxamide
##STR00364##
The title compound was prepared as the HCl salt in 16% overall
yield according to the general procedure for the preparation of
Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 3.27-3.28
(m, 2H), 3.38 (s, 3H), 3.59 (s, 3H), 3.86 (t, J=5.6 Hz, 2H), 4.33
(s, 3H), 7.00 (s, 1H), 7.09 (t, J=10.0 Hz, 2H), 7.36 (d, t, J=8.4
Hz, 1H), 7.46 (t, J=10.0 Hz, 1H), 7.78-7.81 (m, 2H), 8.50 (s, 1H).
[M+H] Calc'd for C.sub.24H.sub.23FN.sub.6O, 431; Found, 431.
Example 32:
[4-(4-cyano-3-fluorophenyl)-1-methyl-5-(2-methyl(2H-indazol-5-yl))pyrrol--
2-yl]-N-[2-(methylamino)ethyl]carboxamide
##STR00365##
The title compound was prepared as the HCl salt in 21% overall
yield according to the general procedure for the preparation of
Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 2.78 (s,
3H), 3.24-3.27 (t, J=6.0 Hz, 2H), 3.68 (t, J=6.0 Hz, 2H), 3.76 (s,
3H), 4.30 (s, 3H), 7.02 (dd, J=2.0, 9.0 Hz, 1H), 7.08 (dd, J=1.2,
10.0 Hz, 1H), 7.24 (s, 1H), 7.27 (dd, J=1.6, 8.8 Hz, 1H), 7.47 (t,
J=8.0 Hz, 1H), 7.74-7.79 (m, 2H), 8.41 (s, 1H). [M+H] Calc'd for
C.sub.24H.sub.23FN.sub.6O, 431; Found, 431.
Example 33: N-[((3S)pyrrolidin-3-yl)methyl]
[4-(4-cyano-3-fluorophenyl)-1-methyl-5-(2-methyl(2H-indazol-5-yl))pyrrol--
2-yl]carboxamide
##STR00366##
The title compound was prepared as the HCl salt in 19% overall
yield according to the general procedure for the preparation of
Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. ppm 1.84-1.89
(m, 1H), 2.20-2.25 (m, 1H), 2.70-2.73 (m, 1H), 3.07-3.12 (m, 1H),
3.30-3.31 (m, 1H), 3.40-3.44 (m, 1H), 3.46-3.49 (m, 3H), 3.73 (s,
3H), 4.34 (s, 3H), 7.02 (dd, J=1.6, 11.2 Hz, 1H), 7.08 (dd, J=2.0,
8.0 Hz, 1H), 7.20-7.22 (m, 1H), 7.37-7.49 (m, 2H), 7.78-7.82 (m,
2H), 8.50 (s, 1H). [M+H] Calc'd for C.sub.26H.sub.25FN.sub.6O, 457;
Found, 457.
Example 34:
(R)-4-(5-(3-aminopiperidine-1-carbonyl)-1-(3-hydroxypropyl)-2-(2-methyl-2-
H-indazol-5-yl)-1H-pyrrol-3-yl)-2-fluorobenzonitrile
##STR00367##
The title compound was prepared as the HCl salt in 25% overall
yield according to the general procedure for the preparation of
Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.61-1.65 (m,
2H), 1.78-1.98 (m, 3H), 2.20-2.30 (m, 1H), 3.28-3.37 (m, 2H),
3.48-3.53 (m, 3H), 4.22-4.27 (m, 3H), 4.42 (s, 3H), 4.48-4.51 (m,
1H), 6.93 (s, 1H), 7.07-7.13 (m, 2H), 7.46-7.58 (m, 2H), 7.87 (d,
J=8.8 Hz, 1H), 7.98 (s, 1H), 8.76 (s, 1H). [M+H] Calc'd for
C.sub.28H.sub.29FN.sub.6O.sub.2, 501; Found, 501.
Example 35:
(R)-4-(5-(3-aminopiperidine-1-carbonyl)-1-(2-hydroxyethyl)-2-(2-methyl-2H-
-indazol-5-yl)-1H-pyrrol-3-yl)-2-fluorobenzonitrile
##STR00368##
The title compound was prepared as the HCl salt in 20% overall
yield according to the general procedure for the preparation of
Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.74-1.92 (m,
3H), 2.20-2.22 (m, 1H), 3.30-3.47 (m, 5H), 4.21-4.29 (m, 3H), 4.35
(s, 3H), 4.53-4.55 (m, 1H), 6.88 (s, 1H), 7.04-7.10 (m, 2H),
7.42-7.46 (m, 2H), 7.81 (d, J=8.8 Hz, 1H), 7.88 (s, 1H), 8.60 (s,
1H). [M+H] Calc'd for C.sub.27H.sub.27FN.sub.6O.sub.2, 487; Found,
487.
Example 36:
(R)-4-(5-(3-aminopiperidine-1-carbonyl)-1-(2-methoxyethyl)-2-(2-methyl-2H-
-indazol-5-yl)-1H-pyrrol-3-yl)-2-fluorobenzonitrile
##STR00369##
The title compound was prepared as the free base in 26% overall
yield according to the general procedure for the preparation of
Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD): .quadrature.
1.76-1.80 (m, 2H), 1.97-1.99 (m, 1H), 2.27-2.29 (m, 1H), 3.18 (s,
3H), 3.25-3.42 (m, 5H), 4.28-4.34 (m, 3H), 4.37 (s, 3H), 4.62-4.65
(m, 1H), 6.91 (s, 1H), 7.09-7.13 (m, 2H), 7.42-7.49 (m, 2H), 7.82
(d, J=8.8 Hz, 1H), 7.88 (s, 1H), 8.59 (s, 1H). [M+H] Calc'd for
C.sub.28H.sub.29FN.sub.6O.sub.2, 501; Found, 501.
Example 37:
(R)-2-(5-(3-aminopiperidine-1-carbonyl)-3-(4-cyano-3-fluorophenyl)-2-(4-m-
ethoxyphenyl)-1H-pyrrol-1-yl)acetamide
##STR00370##
The title compound was prepared as the free base in 25% overall
yield according to the general procedure for the preparation of
Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD): .quadrature.
1.64-1.68 (m, 1H), 1.88-2.14 (m, 3H), 3.41-3.43 (m, 2H), 3.55-3.57
(m, 1H), 3.71-3.75 (m, 1H), 3.88-3.92 (m, 4H), 4.76-4.78 (m, 1H),
5.22-5.25 (m, 1H), 7.04-7.07 (m, 3H), 7.12-7.15 (m, 1H), 7.25 (d,
J=8.4 Hz, 2H), 7.38 (s, 1H), 7.52-7.55 (m, 1H). [M+H] Calc'd for
C.sub.26H.sub.26FN.sub.5O.sub.3, 476; Found, 476.
Example 38:
4-(5-((R)-3-aminopiperidine-1-carbonyl)-1-((R)-2,3-dihydroxypropyl)-2-(2--
methyl-2H-indazol-5-yl)-1H-pyrrol-3-yl)-2-fluorobenzonitrile
##STR00371##
The title compound was prepared as the free base in 21% overall
yield according to the general procedure for the preparation of
Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.75-1.79 (m,
2H), 1.88-1.91 (m, 1H), 2.20-2.22 (m, 1H), 3.21 (d, J=5.2 Hz, 2H),
3.38-3.48 (m, 4H), 4.16-4.27 (m, 3H), 4.37 (s, 3H), 4.49-4.52 (m,
1H), 6.88 (s, 1H), 7.04-7.10 (m, 2H), 7.43-7.51 (m, 2H), 7.81 (d,
J=8.4 Hz, 1H), 7.93 (s, 1H), 8.67 (s, 1H). [M+H] Calc'd for
C.sub.28H.sub.29FN.sub.6O.sub.3, 517; Found, 517.
Example 39:
4-(5-((R)-3-aminopiperidine-1-carbonyl)-1-((S)-2,3-dihydroxypropyl)-2-(2--
methyl-2H-indazol-5-yl)-1H-pyrrol-3-yl)-2-fluorobenzonitrile
##STR00372##
The title compound was prepared as the free base in 18% overall
yield according to the general procedure for the preparation of
Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.75-1.91 (m,
3H), 2.20-2.22 (m, 1H), 3.23 (d, J=5.2 Hz, 2H), 3.38-3.48 (m, 4H),
4.16-4.29 (m, 4H), 4.37 (s, 3H), 6.88 (s, 1H), 7.04-7.10 (m, 2H),
7.43-7.51 (m, 2H), 7.81 (d, J=8.4 Hz, 1H), 7.92 (s, 1H), 8.65 (s,
1H). [M+H] Calc'd for C.sub.28H.sub.29FN.sub.6O.sub.3, 517; Found,
517.
Example 40: N-[((3R)pyrrolidin-3-yl)methyl]
[4-(4-cyano-3-fluorophenyl)-1-methyl-5-(2-methyl(2H-indazol-5-yl))pyrrol--
2-yl]carboxamide
##STR00373##
The title compound was prepared as the hydrochloride salt in 4%
overall yield according to the general procedure for the
preparation of Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 1.86-1.92 (m, 1H), 2.22-2.27 (m, 1H), 2.72-2.75 (m, 1H),
3.09-3.14 (m, 1H), 3.31-3.34 (m, 1H), 3.42-3.51 (m, 4H), 3.74 (s,
3H), 4.31 (s, 3H), 7.04 (dd, J=1.6, 11.6 Hz, 1H), 7.10 (dd, J=1.6,
8.4 Hz, 1H), 7.22 (s, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.46-7.50 (m,
1H), 7.75-7.80 (m, 2H), 8.40 (s, 1H). [M-H] Calc'd for
C.sub.26H.sub.25FN.sub.6O, 457; Found, 457.
Example 41:
4-{5-[((3R)-3-aminopiperidyl)carbonyl]-3-(4-cyano-3-fluorophenyl)-2-(4-me-
thoxyphenyl)pyrrolyl}butanoic acid
##STR00374##
The title compound was prepared as the TFA salt in 3% overall yield
according to the general procedure for the preparation of Example
1. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.60-1.67 (m, 4H),
1.82-1.84 (m, 1H), 1.93-1.97 (m, 2H), 2.10-2.13 (m, 1H), 3.30-3.32
(m, 3H), 3.78 (s, 3H), 3.95-4.02 (m, 2H), 4.18-4.20 (m, 1H),
4.44-4.78 (m, 1H), 6.76 (s, 1H), 6.94-7.00 (m, 4H), 7.13-7.16 (m,
2H), 7.37-7.41 (m, 1H). [M+H] Calc'd for
C.sub.28H.sub.29FN.sub.4O.sub.4, 505; Found, 505.
Example 42:
4-{5-[((3R)-3-aminopiperidyl)carbonyl]-3-(4-cyano-3-fluorophenyl)-2-(4-me-
thoxyphenyl)pyrrolyl}butanamide
##STR00375##
The title compound was prepared as the hydrochloride salt in 2%
overall yield according to the general procedure for the
preparation of Example 1. .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 1.58-1.71 (m, 4H), 1.82-1.92 (m, 3H), 2.10-2.13 (m, 1H),
3.33-3.45 (m, 3H), 3.76 (s, 3H), 3.93-3.99 (m, 2H), 4.05-4.09 (m,
1H), 4.29-4.33 (m, 1H), 6.77 (s, 1H), 6.94-7.00 (m, 4H), 7.13-7.16
(m, 2H), 7.36-7.40 (m, 1H). [M+H] Calc'd for
C.sub.28H.sub.30FN.sub.5O.sub.3, 504; Found, 504.
Preparation 43A: 2-Methyl-5-nitroindazole
##STR00376##
To a solution of 5-nitroindazole (15 g, 91.95 mmol) in ethylacetate
(150 mL), was added BF.sub.4OMe.sub.3 (17.68 g, 119.54 mmol) at
r.t. The mixture was stirred for 5 hr at r.t. aq NaHCO.sub.3 was
added to adjust the pH to 7-8, extracted with ethylacetate, dried,
concentrated to afford the title compound (15 g, 92.5%). [M+H]
Calc'd for C.sub.8H.sub.7N.sub.3O.sub.2, 178; Found, 178.
Preparation 43B: 2-Methylindazol-5-amine
##STR00377##
A mixture of 2-methyl-5-nitroindazole (12 g, 0.0678 mol) and Pd/C
(1.2 g, 10%) in DCM/MeOH (120/120 mL) was stirred for 3 hr at
50.degree. C. with 50 psi of H2. The reaction mixture was then
filtered, concentrated and purified by flash column chromatography
on silica gel (DCM/MeOH=20/1) to afford the title compound (8.414
g, 85%). [M+H] Calc'd for C.sub.8H.sub.9N.sub.3, 148; Found,
148.
Preparation 43C:
4-Bromo-3-fluoro-N-(2-methylindazol-5-yl)benzenecarboximidamide
##STR00378##
To a solution of EtMgBr (30 mL, 27.21 mmol, 0.9 M) in THF (15 mL)
was added a solution of 2-methylindazol-5-amine (2 g, 13.61 mmol)
in THF (20 mL) at r.t. The reaction mixture was stirred for 30 min
at r.t. A solution of 4-bromo-3-fluoro-benzonitrile (2.978 g, 14.97
mmol) in THF (20 mL) was added dropwise at r.t. and stirred
overnight. LC/MS showed the reaction was completed. H.sub.2O was
added and extracted with ethylacetate, dried, concentrated and
purified by flash column chromatography on silica gel (PE/EA=3/1 to
EA) to afford the title compound (3.3 g, 70%). .sup.1H NMR (300
MHz, CDCl.sub.3): .delta. 4.21 (3H, s), 6.98 (1H, dd, J=9.0 Hz,
J=1.8 Hz), 7.13-7.14 (1H, m), 7.60-7.72 (4H, m), 7.80 (11H, s).
[M+H] Calc'd for C.sub.15H.sub.12BrFN.sub.4, 347; Found, 347.
Preparation 43D: Ethyl 3-bromo-2-oxobutanoate
##STR00379##
To a solution of ethyl 2-oxobutanoate (5 g, 38.46 mmol) in DCM was
added Br.sub.2 (6.15 g, 38.46 mmol) dropwise at 0.degree. C., then
stirred for 2 hr at r.t. The reaction mixture was concentrated, the
residue was dissolved in DCM and washed with aq NaHCO.sub.3, dried
and concentrated to give the title compound (7 g, 88%).
Preparation 43E: Ethyl
2-(4-bromo-3-fluorophenyl)-5-methyl-1-(2-methylindazol-5-yl)
imidazole-4-carboxylate
##STR00380##
A mixture of
4-bromo-3-fluoro-N-(2-methylindazol-5-yl)benzenecarboximidamide
(3.3 g, 9.54 mmol), ethyl 3-bromo-2-oxobutanoate (1.983 g, 9.54
mmol) and Na.sub.2CO.sub.3 (1.011 g, 9.54 mmol) in toluene/EtOH (50
mL, 1/1) was stirred overnight at 100.degree. C. It was then
filtered and concentrated. The residue was dissolved in AcOH (20
mL) and stirred for 1 h at 120.degree. C. It was then concentrated
and purified by flash column chromatography on silica gel
(PE/EA=3/1 to EA) to afford the title compound (1.4 g, 32%). [M+H]
Calc'd for C.sub.21H.sub.18BrFN.sub.4O.sub.2, 457; Found, 457.
Preparation 43F: Ethyl
2-(4-cyano-3-fluorophenyl)-5-methyl-1-(2-methylindazol-5-yl)
imidazole-4-carboxylate
##STR00381##
A mixture of ethyl
2-(4-bromo-3-fluorophenyl)-5-methyl-1-(2-methylindazol-5-yl)imidazole-4-c-
arboxylate (1.1 g, 2.41 mmol), Zn(CN).sub.2 (1.41 g, 12.05 mmol)
and Pd(PPh.sub.3).sub.4 (278 mg, 0.241 mmol) in DMA (10 mL) was
stirred overnight at 110.degree. C. in a sealed tube. LC/MS showed
the reaction was completed, concentrated and purified by flash
column chromatography on silica gel (PE/EA=3/1 to EA) to afford the
tile compound (364 mg, 38%). [M+H] Calc'd for
C.sub.22H.sub.18FN.sub.5O.sub.2, 404; Found, 404.
Preparation 43G:
2-(4-Cyano-3-fluorophenyl)-5-methyl-1-(2-methylindazol-5-yl)imidazole-4-c-
arboxylic acid
##STR00382##
To a solution of ethyl
2-(4-cyano-3-fluorophenyl)-5-methyl-1-(2-methylindazol-5-yl)imidazole-4-c-
arboxylate (360 mg, 0.89 mmol) in THF/H.sub.2O (6 mL/2 mL) was
added LiOH--H.sub.2O (187 mg, 4.45 mmol) at r.t, then stirred
overnight at r.t, acidified to pH 3-4, extracted with EA, dried and
concentrated to give the title compound (334 mg, 100%). [M+H]
Calc'd for C.sub.20H.sub.14FN.sub.5O.sub.2, 376; Found, 376.
Example 43:
4-[4-(4-Aminopiperidine-1-carbonyl)-5-methyl-1-(2-methylindazol-5-yl)imid-
azol-2-yl]-2-fluorobenzonitrile
##STR00383##
A mixture of
2-(4-cyano-3-fluorophenyl)-5-methyl-1-(2-methylindazol-5-yl)imidazole-4-c-
arboxylic acid (160 mg, 0.43 mmol), piperidin-4-yl-carbamic acid
tert-butyl ester (85 mg, 0.43 mmol), HATU (178 mg, 0.47 mmol) and
NMM (86 mg, 0.86 mmol) in DMF (5 mL) was stirred for 1 hr at r.t,
LC/MS showed the reaction was completed, concentrated to afford the
boc protected intermediate (239 mg, 100%). A solution of the
intermediate (239 mg, 0.43 mmol) in HCl/EA (5 mL) was stirred for 1
hr at r.t. LC/MS showed the reaction was completed, concentrated
and purified by prep-HPLC to afford the title compound (107 mg,
55%). .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.61-1.64 (2H, m),
2.07-2.10 (2H, m), 2.20 (3H, s), 3.20-3.22 (2H, m), 3.40-3.42 (1H,
m), 4.19 (3H, s), 4.20-4.60 (2H, m), 7.32-7.46 (3H, m), 7.66-7.74
(2H, m), 7.95 (1H, s), 8.37 (1H, s). [M+H] Calc'd for
C.sub.25H.sub.24FN.sub.7O, 458; Found, 458.
Example 44:
N-(2-Aminoethyl)-2-(4-cyano-3-fluorophenyl)-N,5-dimethyl-1-(2-methylindaz-
ol-5-yl)imidazole-4-carboxamide
##STR00384##
The title compound was prepared as TFA salt in 3% overall yield
according to the general procedure for the preparation of Example
43. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 2.34 (3H, s),
3.33-3.40 (5H, m), 3.94-3.95 (2H, m), 4.33 (3H, s), 7.47-7.60 (3H,
m), 7.85-7.88 (2H, m), 8.08 (1H, s), 8.53 (1H, s). [M+H] Calc'd for
C.sub.23H.sub.22FN.sub.7O, 432; Found, 432.
Example 45:
2-(4-Cyano-3-fluorophenyl)-5-methyl-1-(2-methylindazol-5-yl)-N-piperidin--
3-ylimidazole-4-carboxamide
##STR00385##
The title compound was prepared as TFA salt in 2% overall yield
according to the general procedure for the preparation of Example
43. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.89-1.94 (2H, m),
2.17-2.18 (2H, m), 2.49 (3H, s), 3.15-3.20 (2H, m), 3.33-3.36 (1H,
m), 3.55-3.59 (1H, m), 4.35-4.37 (4H, m), 7.44-7.50 (2H, m),
7.61-7.64 (1H, m), 7.77-7.80 (1H, m), 7.88-7.91 (1H, m), 8.04 (1H,
s), 8.59 (1H, s). [M+H] Calc'd for C.sub.25H.sub.24FN.sub.7O, 458;
Found, 458.
Example 46:
2-(4-Cyano-3-fluorophenyl)-5-methyl-1-(2-methylindazol-5-yl)-N-pyrrolidin-
-3-ylimidazole-4-carboxamide
##STR00386##
The title compound was prepared as TFA salt in 3% overall yield
according to the general procedure for the preparation of Example
43. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 2.27-2.28 (1H, m),
2.43-2.48 (4H, m), 3.43-3.50 (2H, m), 3.61-3.65 (2H, m), 4.31 (3H,
s), 4.70-4.72 (1H, m), 7.38 (1H, d, J=9.2 Hz), 7.43 (1H, d, J=8.0
Hz), 7.58 (1H, d, J=9.6 Hz), 7.74 (1H, t, J=7.2 Hz), 7.85 (1H, d,
J=9.2 Hz), 7.96 (1H, s), 8.52 (1H, s). [M+H] Calc'd for
C.sub.24H.sub.22FN.sub.7O, 444; Found, 444.
Preparation 47A: N-(5-Fluoro-2-methylphenyl)acetamide
##STR00387##
A solution of 5-fluoro-2-methylaniline (5 g, 0.04 mol), Ac.sub.2O
(4.08 g, 0.04 mol) and TEA (4.848 g, 0.048 mol) in DCM (20 mL) was
stirred overnight at rt. H.sub.2O was added, extracted with DCM,
dried, concentrated to afford the title compound (6 g, 90%). [M+H]
Calc'd for C.sub.9H.sub.10FNO, 168; Found, 168.
Preparation 47B: N-(5-Fluoro-2-methyl-4-nitrophenyl)acetamide
##STR00388##
To a solution of N-(5-fluoro-2-methylphenyl)acetamide (6 g, 3.593
mmol) in 98% H.sub.2SO.sub.4 (36 mL) was added 70% HNO.sub.3 (3.23
g, 3.593 mmol) at 0.degree. C., then the mixture was stirred for 1
hr at this temperature. TLC showed the reaction was completed,
poured into ice water and extracted with DCM, dried, concentrated
to afford the title compound (6 g, 79%). [M+H] Calc'd for
C.sub.9H9FN.sub.2O.sub.3, 213; Found, 213.
Preparation 47C: 5-Fluoro-2-methyl-4-nitroaniline
##STR00389##
A solution of N-(5-fluoro-2-methyl-4-nitrophenyl)acetamide (6 g,
35.93 mmol) in 5N HCl (30 mL) was stirred for 1 hr at 100.degree.
C., TLC showed the reaction was completed, cooled and adjusted to
pH=7-8 with Na.sub.2CO.sub.3, extracted with EA, dried,
concentrated to afford the title compound (4.9 g, 80%). [M+H]
Calc'd for C.sub.7H.sub.7FN.sub.2O.sub.2, 171; Found, 171.
Preparation 47D: 6-Fluoro-5-nitro-1H-indazole
##STR00390##
To a solution of 5-fluoro-2-methyl-4-nitroaniline (4.9 g, 28.82
mmol) in AcOH (50 mL) was added NaNO.sub.2 (2.18 g, 31.71 mmol) in
water (5 mL) in ice-bath. The mixture was stirred for 2 hr in
ice-bath. H.sub.2O was added and extracted with EA, dried,
concentrated and purified by flash chromatography on silica gel
(PE/EA=3/1) to afford the title compound (1.14 g, 21%). .sup.1H NMR
(300 MHz, DMSO): .delta. 7.86 (1H, d, J=12.0 Hz), 8.36 (1H, s),
8.76 (1H, d, J=7.2 Hz), 13.71 (1H, s). [M+H] Calc'd for
C.sub.7H.sub.4FN.sub.3O.sub.2, 182; Found, 182.
Preparation 47E: 6-Fluoro-2-methyl-5-nitroindazole
##STR00391##
To a solution of 6-fluoro-5-nitro-1H-indazole (1.14 g, 6.30 mmol)
in EA (150 mL) was added BF.sub.4--OMe.sub.3 (1.397 g, 9.45 mmol)
at rt. The mixture was stirred for 5 hr at r.t. aq NaHCO.sub.3 was
added to adjust pH=7-8, extracted with EA, dried, concentrated to
afford the title compound (1 g, 81%). [M+H] Calc'd for
C.sub.8H.sub.6FN.sub.3O.sub.2, 196; Found, 196.
Preparation 47F: 6-Fluoro-2-methylindazol-5-amine
##STR00392##
A mixture of 6-fluoro-2-methyl-5-nitroindazole (1 g, 5.128 mol) and
Pd/C (200 mg, 10%) in DCM/MeOH (10/10 mL) was stirred overnight at
r.t. under H.sub.2. LC/MS showed the reaction was completed,
filtered, concentrated and purified by flash chromatography on
silica gel (DCM/MeOH=20/1) to afford the title compound (400 mg,
47%). [M+H] Calc'd for C.sub.8H.sub.8FN.sub.3, 166; Found, 166.
Preparation 47G:
4-Bromo-3-fluoro-N-(6-fluoro-2-methylindazol-5-yl)benzenecarboximidamide
##STR00393##
To a solution of 6-fluoro-2-methylindazol-5-amine (100 mg, 0.61
mmol) in toluene (5 mL) was added a solution of Al(CH.sub.3).sub.3
(0.5 mL, 0.91 mmol) in THF at 0.degree. C., then the mixture was
stirred for 3.5 hr at r.t. A solution of
4-bromo-3-fluoro-benzonitrile (241 mg, 1.21 mmol) in THF (5 mL) was
added dropwised at r.t. and stirred overnight at 75.degree. C.
LC/MS showed the reaction was completed, after concentration, the
residue was purified by flash chromatography on silica gel
(PE/EA=3/1 to EA) to afford the title compound (120 g, 54%). [M+H]
Calc'd for C.sub.15H.sub.11BrF.sub.2N.sub.4, 365; Found, 365.
Example 47:
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-1-(6-fluoro-2-methylindazol-5-yl-
)-5-methylimidazol-2-yl]-2-fluorobenzonitrile
##STR00394##
The title compound was prepared as TFA salt in 1% overall yield
according to the general procedure for the preparation of Example
43 using
4-bromo-3-fluoro-N-(6-fluoro-2-methylindazol-5-yl)benzenecarboximidamide.
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.74-2.00 (3H, m),
2.19-2.29 (4H, m), 3.40-3.54 (3H, m), 4.12-4.48 (5H, m), 7.39-7.42
(1H, m), 7.56-7.60 (2H, m), 7.72-7.77 (1H, m), 8.17-8.20 (1H, m),
8.48 (1H, s). [M+H] Calc'd for C.sub.25H.sub.23F.sub.2N.sub.7O,
476; Found, 476.
Example 48:
4-[4-[(3S)-3-(Dimethylamino)pyrrolidine-1-carbonyl]-1-(6-fluoro-2-methyli-
ndazol-5-yl)-5-methylimidazol-2-yl]-2-fluorobenzonitrile
##STR00395##
The title compound was prepared as TFA salt in 0.4% overall yield
according to the procedure for the preparation of Example 47.
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 2.25-2.29 (4H, m),
2.53-2.55 (1H, m), 3.01 (6H, s), 4.00-4.15 (4H, m), 4.25 (3H, s),
4.49-4.55 (1H, m), 7.27-7.29 (1H, m), 7.42-7.62 (3H, m), 7.91-7.97
(1H, m), 8.41 (1H, s). [M+H] Calc'd for
C.sub.26H.sub.25F.sub.2N.sub.7O, 490; Found, 490.
Example 49:
2-Fluoro-4-[1-(6-fluoro-2-methylindazol-5-yl)-5-methyl-4-[(3S)-3-(methyla-
mino)pyrrolidine-1-carbonyl]imidazol-2-yl]benzonitrile
##STR00396##
The title compound was prepared as TFA salt in 0.2% overall yield
according to the procedure for the preparation of example 47.
.sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 2.30-2.51 (5H, m), 2.82
(3H, s), 3.91-4.41 (8H, m), 7.37-7.70 (4H, m), 8.15 (1H, br), 8.52
(1H, s). [M+H] Calc'd for C.sub.25H.sub.23F.sub.2N.sub.7O, 476;
Found, 476.
Preparation 50A: 7-Fluoro-5-nitro-1H-indazole and
7-fluoro-4-nitro-1H-indazole
##STR00397##
To a solution of 7-fluoro-1H-indazole (7.2 g, 52.99 mmol) in 98%
H.sub.2SO.sub.4 (70 mL) was added KNO.sub.3 (5.62 g, 55.64 mmol)
portionwise at 0.degree. C., allow the reaction mixture to stir for
4 hr at the same temperature; then poured into ice-water, extracted
with EA, the combined organic layers were washed by H.sub.2O, aq
NaHCO.sub.3, and dried over Na.sub.2SO.sub.4, after concentration
the residue was purified by flash chromatography on silica gel
(PE/EA=3/1) to afford a mixture of 7-fluoro-5-nitro-1H-indazole and
7-fluoro-4-nitro-1H-indazole (8.23 g, 86%).
Preparation 50B: 7-Fluoro-2-methyl-5-nitroindazole and
7-fluoro-2-methyl-4-nitroindazole
##STR00398##
To a solution of a mixture of 7-fluoro-5-nitro-1H-indazole and
7-fluoro-4-nitro-1H-indazole (8.23 g, 45.47 mmol) in EA (100 mL)
was added BF.sub.4--OMe.sub.3 (10.08 g, 68.20 mmol) at r.t. The
mixture was stirred for 5 hr at r.t. aq NaHCO.sub.3 was added to
adjust pH=7-8, the reaction mixture was extracted with EA, the
combined organic layers were dried over Na.sub.2SO.sub.4, the
solvent was removed in vacuum to afford a mixture of compound
7-fluoro-2-methyl-5-nitroindazole and
7-fluoro-2-methyl-4-nitroindazole (3.2 g, 36%). [M+H] Calc'd for
C.sub.8H6FN.sub.3O.sub.2, 196; Found, 196.
Preparation 50C: 7-Fluoro-2-methylindazol-5-amine and
7-fluoro-2-methylindazol-4-amine
##STR00399##
A mixture of 7-fluoro-2-methyl-5-nitroindazole and
7-fluoro-2-methyl-4-nitroindazole (3.2 g, 16.41 mol), Fe (9.2 g,
164 mmol), and NH.sub.4Cl (439 mg, 8.20 mmol) in 80% EtOH (30 mL)
was refluxed for 4 hr. LC/MS showed the reaction was completed. The
mixture was filtered and concentrated, the residue was purified by
flash chromatography on silica gel (PE/EA=1/1) to afford a mixture
of 7-fluoro-2-methylindazol-5-amine (326 mg) and
7-fluoro-2-methylindazol-4-amine (724 mg).
7-Fluoro-2-methylindazol-5-amine: .sup.1H NMR (400 MHz, DMSO):
.delta. 4.06 (3H, s), 4.96 (2H, s), 6.39 (1H, J=1.2 Hz, d), 6.53
(1H, J=13.6 Hz, 1.2 Hz, dd), 7.96 (1H, J=2.8 Hz, d). [M+H] Calc'd
for C.sub.8H.sub.8FN.sub.3, 166; Found, 166.
7-fluoro-2-methylindazol-4-amine: .sup.1H NMR (400 MHz, DMSO):
.delta. 4.12 (3H, s), 5.41 (2H, s), 5.84 (1H, J=8.0 Hz, 2.8 Hz,
dd), 6.67 (1H, J=12 Hz, 7.6 Hz, dd), 8.32 (1H, J=2.8 Hz, d). [M+H]
Calc'd for C.sub.8H.sub.8FN.sub.3, 166; Found, 166.
Example 50:
4-[4-[(3S)-3-Aminopyrrolidine-1-carbonyl]-1-(7-fluoro-2-methylindazol-5-y-
l)-5-methylimidazol-2-yl]-2-fluorobenzonitrile
##STR00400##
The title compound was prepared as TFA salt in 0.2% overall yield
according to the procedure for the preparation of example 47 using
7-fluoro-2-methylindazol-5-amine. .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 2.15-2.23 (1H, m), 2.36 (3H, s), 2.47-2.48
(1H, m), 3.77-4.34 (8H, m), 7.18 (1H, d, J=11.1 Hz), 7.38 (1H, d,
J=7.8 Hz), 7.54 (1H, d, J=10.2 Hz), 7.67-7.74 (2H, m), 8.49 (1H,
s). [M+H] Calc'd for C.sub.24H.sub.21F.sub.2N.sub.7O, 462; Found,
462.
Example 51:
2-Fluoro-4-[1-(7-fluoro-2-methylindazol-5-yl)-5-methyl-4-[(3S)-3-(methyla-
mino)pyrrolidine-1-carbonyl]imidazol-2-yl]benzonitrile
##STR00401##
The title compound was prepared as TFA salt in 0.2% overall yield
according to the procedure for the preparation of example 47
7-fluoro-2-methylindazol-5-amine. .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 2.22-2.52 (2H, m), 2.36 (3H, s), 2.79 (3H, s),
3.85-4.40 (8H, m), 7.13-7.17 (1H, m), 7.35-7.37 (1H, m), 7.49-7.74
(3H, m), 8.48 (1H, s). [M+H] Calc'd for
C.sub.25H.sub.23F.sub.2N.sub.7O, 476; Found, 476.
Example 52:
4-[4-[(3S)-3-(Dimethylamino)pyrrolidine-1-carbonyl]-1-(7-fluoro-2-methyli-
ndazol-5-yl)-5-methylimidazol-2-yl]-2-fluorobenzonitrile
##STR00402##
The title compound was prepared as TFA salt in 0.2% overall yield
according to the procedure for the preparation of example 47 using
7-fluoro-2-methylindazol-5-amine. 1H NMR (400 MHz, CD.sub.3OD):
.delta. 2.22-2.52 (4H, m), 2.50-2.70 (1H, m), 3.03 (6H, s),
3.76-4.57 (8H, m), 7.22-7.24 (1H, m), 7.46-7.59 (2H, m), 7.75-7.90
(2H, m), 8.53 (1H, s). [M+H] Calc'd for
C.sub.26H.sub.25F.sub.2N.sub.7O, 490; Found, 490.
Preparation 53A: Ethyl
1-(3-chloro-2-methylindazol-5-yl)-2-(4-cyano-3-fluorophenyl)-5-methylimid-
azole-4-carboxylate
##STR00403##
To a solution of ethyl
2-(4-cyano-3-fluorophenyl)-5-methyl-1-(2-methylindazol-5-yl)imidazole-4-c-
arboxylate (100 mg, 0.248 mmol) in ACN (10 mL) was added NCS (33
mg, 0.248 mmol) at r.t. The mixture was stirred overnight at
50.degree. C. H.sub.2O was added and extracted with DCM, dried,
concentrated to afford the title compound (90 mg, 83%). .sup.1H NMR
(300 MHz, CDCl.sub.3): .delta. 1.46 (3H, t, J=7.2 Hz), 2.43 (3H,
s), 4.25 (3H, s), 4.47 (2H, q, J=7.2 Hz), 7.28-7.29 (1H, m),
7.41-7.45 (4H, m), 7.81-7.84 (1H, m). [M+H] Calc'd for
C.sub.22H.sub.17ClFN.sub.5O.sub.2, 438; Found, 438.
Preparation 53B:
1-(3-Chloro-2-methylindazol-5-yl)-2-(4-cyano-3-fluorophenyl)-5-methylimid-
azole-4-carboxylic acid
##STR00404##
To a solution of ethyl
1-(3-chloro-2-methylindazol-5-yl)-2-(4-cyano-3-fluorophenyl)-5-methylimid-
azole-4-carboxylate (180 mg, 0.41 mmol) in THF/H.sub.2O (6 mL/2 mL)
was added LiOH.H.sub.2O (35 mg, 0.82 mmol) at rt, then stirred for
overnight at rt, acidified to pH=3-4, and extracted with EA, dried
and concentrated to give the title compound (170 mg, 100%). [M+H]
Calc'd for C.sub.20H.sub.13ClFN.sub.5O.sub.2, 410; Found, 410.
Example 53:
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-1-(3-chloro-2-methylindazol-5-yl-
)-5-methylimidazol-2-yl]-2-fluorobenzonitrile
##STR00405##
The title compound was prepared as TFA salt in 37% overall yield
according to the procedure for the preparation of example 47
starting from ethyl
1-(2-methylindazol-5-yl)-2-(4-cyano-3-fluorophenyl)-5-methylimidazole-4-c-
arboxylate. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.63-1.66
(2H, m), 1.70-1.75 (1H, m), 2.05-2.06 (1H, m), 2.14 (3H, s),
3.29-3.33 (3H, m), 3.99-4.07 (1H, m), 4.08 (3H, s), 4.20-4.30 (1H,
m), 7.19-7.24 (2H, m), 7.30-7.40 (1H, m), 7.54-7.57 (1H, m),
7.66-7.71 (2H, m). [M+H] Calc'd for C.sub.25H.sub.23ClFN.sub.7O,
492; Found, 492.
Example 54:
4-[1-(3-Chloro-2-methylindazol-5-yl)-5-methyl-4-[(3S)-3-(methylamino)pyrr-
olidine-1-carbonyl]imidazol-2-yl]-2-fluorobenzonitrile
##STR00406##
The title compound was prepared as TFA salt in 23% overall yield
according to the procedure for the preparation of example 53.
.sup.1HNMR (400 MHz, CD.sub.3OD): .delta. 2.37-2.39 (4H, m),
2.55-2.64 (1H, m), 2.85 (3H, s), 3.79-4.38 (5H, m), 4.25 (3H, s),
7.49-7.63 (3H, m), 7.80-7.86 (2H, m), 7.99 (1H, s). [M+H] Calc'd
for C.sub.25H.sub.23ClFN.sub.7O, 492; Found, 492.
Example 55:
4-[1-(3-Chloro-2-methylindazol-5-yl)-5-methyl-4-[(3R)-3-(methylamino)pipe-
ridine-1-carbonyl]imidazol-2-yl]-2-fluorobenzonitrile
##STR00407##
The title compound was prepared as TFA salt in 7% overall yield
according to the procedure for the preparation of example 53.
.sup.1HNMR (400 MHz, CD.sub.3OD): .delta. 1.77-2.07 (3H, m),
2.33-2.34 (4H, m), 2.83 (3H, s), 3.40-3.41 (1H, m), 3.79-4.50 (4H,
m), 4.25 (3H, s), 7.50-7.64 (3H, m), 7.81-7.85 (2H, m), 8.03 (1H,
s). [M+H] Calc'd for C.sub.26H.sub.25ClFN.sub.7O, 506; Found,
506.
Example 56:
1-(3-Chloro-2-methylindazol-5-yl)-2-(4-cyano-3-fluorophenyl)-5-methyl-N-[-
(3R)-1-methylpiperidin-3-yl]imidazole-4-carboxamide
##STR00408##
The title compound was prepared as TFA salt in 7% overall yield
according to the procedure for the preparation of example 53.
.sup.1HNMR (300 MHz, CD.sub.3OD): .delta. 1.70-2.14 (4H, m), 2.41
(3H, s), 2.88-2.99 (2H, m), 2.94 (3H, s), 3.53-3.68 (2H, m), 4.21
(3H, s), 4.22-4.28 (1H, m), 7.20-7.28 (2H, m), 7.49-7.60 (2H, m),
7.70 (1H, s), 7.80 (1H, d, J=9.0 Hz). [M+H] Calc'd for
C.sub.26H.sub.25ClFN.sub.7O, 506; Found, 506.
Preparation 57A: 3-Chloro-2-methyl-5-nitroindazole
##STR00409##
A solution of 2-methyl-5-nitroindazole (9 g, 50.85 mmol) and NCS
(6.79 g, 50.85 mmol) in AcOH (60 mL) was stirred overnight at
70.degree. C. Concentrated and dissolved in EA, washed by aq
NaHCO.sub.3 and H.sub.2O, dried over Na.sub.2SO.sub.4, concentrated
in vacuum to afford the title compound (10.7 g, 100%). .sup.1HNMR
(300 MHz, CDCl.sub.3): .delta. 4.22 (3H, s), 7.69 (1H, d, J=9.6
Hz), 8.10 (1H, dd, J=9.6 Hz, 2.1 Hz), 8.62 (1H, d, J=1.8 Hz).
Preparation 57B: 3-Chloro-2-methylindazol-5-amine
##STR00410##
A mixture of 3-chloro-2-methyl-5-nitroindazole (10.7 g, 50.85
mmol), Fe (28.40 g, 508.5 mmol) and NH.sub.4Cl (1.36 g, 25.35 mmol)
in 80% EtOH (100 mL) was refluxed for 4 hr. LCMS showed the
reaction was completed, after filtration, the residue was
concentrated to afford the title compound (9.2 g, 100%). [M+H]
Calc'd for C.sub.8H.sub.8ClN.sub.3, 182; Found, 182.
Example 57:
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-[(3S)-3-(dimethylamino)pyrrolidine-
-1-carbonyl]imidazol-2-yl]-2-fluorobenzonitrile
##STR00411##
The title compound was prepared as TFA salt in 23% overall yield
according to the procedure for the preparation of Example 47 using
3-chloro-2-methylindazol-5-amine. .sup.1HNMR (400 MHz, CD.sub.3OD):
.delta. 2.36-2.65 (2H, m), 3.08 (6H, s), 3.86-4.25 (4H, m), 4.25
(3H, s), 4.62-4.90 (1H, m), 7.23-7.38 (2H, m), 7.52-7.69 (2H, m),
7.74-7.78 (2H, m), 8.12-8.15 (1H, m). [M+H] Calc'd for
C.sub.25H.sub.23ClFN.sub.7O, 492; Found, 492.
Example 58:
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-[(3S)-3-(dimethylamino)pyrrolidine-
-1-carbonyl]-5-fluoroimidazol-2-yl]-2-fluorobenzonitrile
##STR00412##
A solution of
4-[1-(3-chloro-2-methylindazol-5-yl)-4-[(3S)-3-(dimethylamino)pyrrolidine-
-1-carbonyl]imidazol-2-yl]-2-fluorobenzonitrile (500 mg, 1.02 mmol)
and selectflour (720 mg, 2.04 mmol) in ACN was stirred overnight at
70.degree. C. under N.sub.2, after concentration the residue was
purified by prep-HPLC to give the title compound (7 mg, 1%).
.sup.1HNMR (400 MHz, CD.sub.3OD): .delta. 2.20-2.28 (2H, m), 3.01
(6H, s), 3.55-4.71 (5H, m), 4.22 (3H, s), 7.24-7.29 (2H, m),
7.46-7.47 (1H, m), 7.58-7.63 (1H, m), 7.77-7.84 (2H, m). [M+H]
Calc'd for C.sub.25H.sub.22ClF.sub.2N.sub.7O, 510; Found, 510.
Example 59:
1-(3-Chloro-2-methylindazol-5-yl)-2-(4-cyano-3-fluorophenyl)-N-[(3R)-1-me-
thylpiperidin-3-yl]imidazole-4-carboxamide
##STR00413##
The title compound was prepared as TFA salt in 5% overall yield
according to the procedure for the preparation of Example 57.
.sup.1HNMR (300 MHz, CD.sub.3OD): .delta. 1.70-2.14 (4H, m),
2.89-2.99 (2H, m), 2.94 (3H, s), 3.52-3.70 (2H, m), 4.21 (3H, s),
4.30-4.32 (1H, m), 7.19-7.33 (2H, m), 7.52-7.75 (4H, m), 8.02 (1H,
s). [M+H] Calc'd for C.sub.25H.sub.23ClFN.sub.7O, 492; Found,
492.
Example 60:
2-(4-Cyano-3-fluorophenyl)-5-methyl-1-(2-methylindazol-5-yl)-N-[(3R)-1-me-
thylpiperidin-3-yl]imidazole-4-carboxamide
##STR00414##
The title compound was prepared as TFA salt in 5% overall yield
according to the general procedure for the preparation of Example
43. .sup.1HNMR (400 MHz, CD.sub.3OD): .delta. 1.64-2.15 (4H, m),
2.41 (3H, s), 2.93-2.97 (2H, m), 2.94 (3H, s), 3.56-3.67 (2H, m),
4.26 (3H, s), 4.26-4.28 (1H, m), 7.16-7.29 (2H, m), 7.45-7.59 (2H,
m), 7.74-7.93 (2H, m), 8.35 (1H, s). [M+H] Calc'd for
C.sub.26H.sub.26FN.sub.7O, 472; Found, 472.
Example 61:
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-1-(3-chloro-2-methylindazol-5-yl-
)-5-fluoroimidazol-2-yl]-2-fluorobenzonitrile
##STR00415##
The title compound was prepared as TFA salt in 3% yield according
to the procedure for the preparation of Example 58. .sup.1H NMR
(400 MHz, CD.sub.3OD): .delta. 1.30-1.43 (2H, m), 1.77-1.80 (1H,
m), 1.97-2.02 (1H, m), 2.85-2.88 (2H, m), 3.20-3.25 (1H, m), 4.13
(3H, s), 4.13-4.61 (2H, m), 7.16-7.22 (2H, m), 7.13-7.14 (1H, m),
7.52 (1H, t, J=7.4 Hz), 7.68 (1H, d, J=8.8 Hz), 7.76 (1H, s). [M+H]
Calc'd for C.sub.24H.sub.20ClF.sub.2N.sub.7O, 496; Found, 496.
Example 62:
2-(4-Cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)-5-methyl-N-[(3R)--
piperidin-3-yl]imidazole-4-carboxamide
##STR00416##
The title compound was prepared as TFA salt in 0.2% overall yield
according to the general procedure for the preparation of Example
12. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.87-1.88 (2H, m),
2.11-2.14 (2H, m), 2.43 (3H, s), 3.09-3.12 (2H, m), 3.30-3.33 (2H,
m), 3.96 (3H, s), 4.25-4.40 (1H, m), 7.25-7.42 (4H, m), 7.57-7.60
(1H, m), 7.77-7.81 (1H, m). [M+H] Calc'd for
C.sub.24H.sub.23F.sub.2N.sub.5O.sub.2, 452; Found, 452.
Example 63:
2-(4-Cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)-5-methyl-N-[(3S)--
piperidin-3-yl]imidazole-4-carboxamide
##STR00417##
The title compound was prepared as TFA salt in 0.2% overall yield
according to the general procedure for the preparation of Example
12. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.87-1.88 (2H, m),
2.11-2.14 (2H, m), 2.43 (3H, s), 3.09-3.12 (2H, m), 3.30-3.33 (2H,
m), 3.96 (3H, s), 4.25-4.40 (1H, m), 7.25-7.42 (4H, m), 7.57-7.60
(1H, m), 7.77-7.81 (1H, m). [M+H] Calc'd for
C.sub.24H.sub.23F.sub.2N.sub.5O.sub.2, 452; Found, 452.
Example 64:
2-Fluoro-4-[1-(3-fluoro-4-methoxyphenyl)-5-methyl-4-[(3S)-3-(methylamino)-
pyrrolidine-1-carbonyl]imidazol-2-yl]benzonitrile
##STR00418##
The title compound was prepared as TFA salt in 1% overall yield
according to the general procedure for the preparation of Example
12. .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 2.18-2.32 (4H, m),
2.50-2.52 (1H, m), 2.80 (3H, s), 3.93-4.35 (5H, m), 3.96 (3H, s),
7.24-7.38 (4H, m), 7.49-7.52 (1H, m), 7.72-7.77 (1H, m). [M+H]
Calc'd for C.sub.24H.sub.23F.sub.2N.sub.5O.sub.2, 452; Found,
452.
Example 65:
2-Fluoro-4-[1-(3-fluoro-4-methoxyphenyl)-4-[(3S)-3-(methylamino)pyrrolidi-
ne-1-carbonyl]imidazol-2-yl]benzonitrile
##STR00419##
The title compound was prepared as TFA salt in 0.6% overall yield
according to the general procedure for the preparation of Example
12 using ethyl bromopyruvate. .sup.1H NMR (300 MHz, CD.sub.3OD):
.delta. 2.18-2.32 (2H, m), 2.81 (3H, s), 3.93-4.35 (5H, m), 3.94
(3H, s), 7.23-7.40 (4H, m), 7.55-7.58 (1H, m), 7.80-7.82 (1H, m);
8.23-8.27 (1H, m). [M+H] Calc'd for
C.sub.23H.sub.21F.sub.2N.sub.5O.sub.2, 438; Found, 438.
Preparation 66A:
4-Bromo-3-fluoro-N-(3-fluoro-4-methoxyphenyl)benzenecarboximidamide
##STR00420##
To a solution of EtMgBr (48 mL, 42.55 mmol, 0.9 M) in THF (24 mL)
was added a solution of 3-fluoro-4-methoxyaniline (3 g, 21.28 mmol)
in THF (30 mL) at r.t. The mixture was stirred for 30 min at r.t. A
solution of 4-bromo-3-fluorobenzonitrile (4.657 g, 23.40 mmol) in
THF (20 mL) was added dropwise at r.t. and stirred overnight at
r.t. LC/MS showed the reaction was completed, H.sub.2O was added
and extracted with EA, dried, concentrated and purified by flash
chromatography on silica gel (PE/EA=3/1 to EA) to afford
4-bromo-3-fluoro-N-(3-fluoro-4-methoxyphenyl)benzenecarboximidamide
(4.68 g, 65%). [M+H] Calc'd for C.sub.14H.sub.11BrF.sub.2N.sub.2O,
341; Found, 341.
Preparation 66B: Ethyl
2-(4-bromo-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)imidazole-4-carbox-
ylate
##STR00421##
A mixture of
4-bromo-3-fluoro-N-(3-fluoro-4-methoxyphenyl)benzenecarboximidamide
(4.68 g, 13.76 mmol), ethyl 3-bromo-2-oxopropanoate (2.684 g, 13.76
mmol) and Na.sub.2CO.sub.3 (1.459 g, 13.76 mmol) in toluene/EtOH
(100 mL, 1/1) was stirred overnight at 100.degree. C.; filtered,
concentrated, the residue was dissolved in AcOH (50 mL) and stirred
for 1 h at 120.degree. C., concentrated and purified by flash
chromatography on silica gel (PE/EA=3/1 to EA) to afford the title
compound (1.1 g, 18%). [M+H] Calc'd for
C.sub.19H.sub.15BrF.sub.2N.sub.2O.sub.3, 437; Found, 437.
Preparation 66C: Ethyl
2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)imidazole-4-carbox-
ylate
##STR00422##
A mixture of ethyl
2-(4-bromo-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)imidazole-4-carbox-
ylate (1.1 g, 2.58 mmol), Zn(CN)2 (1.51 g, 12.89 mmol) and
Pd(PPh.sub.3).sub.4 (298 mg, 0.258 mmol) in DMA (5 mL) was stirred
overnight at 110.degree. C. in a sealed tube. LC/MS showed the
reaction was completed, concentrated and purified by flash
chromatography on silica gel (PE/EA=3/1 to EA) to afford the title
compound (600 mg, 60%). [M+H] Calc'd for
C.sub.20H.sub.15F.sub.2N.sub.3O.sub.3, 384; Found, 384.
Preparation 66D: Ethyl
5-chloro-2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)
imidazole-4-carboxylate
##STR00423##
To a solution of ethyl
2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)imidazole-4-carbox-
ylate (200 mg, 0.522 mmol) in AcOH (5 mL) was added NCS (70 mg,
0.522 mmol) at r.t, then stirred overnight at 50.degree. C.;
concentrated, H.sub.2O was added and extracted with DCM, dried and
concentrated to give the title compound (196 mg, 90%). [M+H] Calc'd
for C.sub.20H.sub.14ClF.sub.2N.sub.3O.sub.3, 418; Found, 418.
Preparation 66E:
5-Chloro-2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)imidazole-
-4-carboxylic acid
##STR00424##
To a solution of Ethyl
5-chloro-2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)imidazole-
-4-carboxylate (196 mg, 0.47 mmol) in THF/H.sub.2O (6 mL/2 mL) was
added LiOH.H.sub.2O (100 mg, 2.35 mmol) at r.t, stirred overnight
at r.t, acidified to pH=3-4, extracted with EA, dried and
concentrated to give the title compound (182 mg, 100%). [M+H]
Calc'd for C.sub.18H.sub.10ClF.sub.2N.sub.3O.sub.3, 390; Found,
390.
Preparation 66F: tert-butyl
N-[(3R)-1-[5-Chloro-2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxypheny-
l)imidazole-4-carbonyl]piperidin-3-yl]carbamate
##STR00425##
A mixture of
5-chloro-2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)imidazole-
-4-carboxylic acid (180 mg, 0.46 mmol),
N-((3R)(3-piperidyl))(tert-butoxy) carboxamide (93 mg, 0.46 mmol),
HATU (194 mg, 0.51 mmol) and NMM (94 mg, 0.93 mmol) in DMF (5 mL)
was stirred for 1 hr at r.t. LC/MS showed the reaction was
completed, concentrated to afford the title compound (260 mg,
100%). [M+H] Calc'd for C.sub.28H.sub.28ClF.sub.2N.sub.5O.sub.4,
572; Found, 572.
Example 66:
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5-chloro-1-(3-fluoro-4-methoxyph-
enyl)imidazol-2-yl]-2-fluorobenzonitrile
##STR00426##
A solution of tert-butyl
N-[(3R)-1-[5-Chloro-2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxypheny-
l)imidazole-4-carbonyl]piperidin-3-yl]carbamate (260 mg, 0.46 mmol)
in HCl/EA (5 mL) was stirred for 1 hr at r.t. LC/MS showed the
reaction was completed, concentrated and purified by prep-HPLC to
afford the title compound (117 mg, 54%). .sup.1H NMR (400 MHz,
CD.sub.3OD): .delta. 1.65-1.67 (2H, m), 1.83-1.84 (1H, m),
2.08-2.09 (1H, m), 3.19-3.30 (3H, m), 3.86 (3H, s), 3.90-4.37 (2H,
m), 7.06-7.37 (5H, m), 7.60 (1H, t, J=7.2 Hz). [M+H] Calc'd for
C.sub.23H.sub.20ClF.sub.2N.sub.5O.sub.2, 472; Found, 472.
Preparation 67A:
2-(4-Cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)imidazole-4-carbox-
ylic acid
##STR00427##
To a solution of ethyl
2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)imidazole-4-carbox-
ylate (300 mg, 0.78 mmol) in THF/H.sub.2O (9 mL/3 mL) was added
LiOH.H.sub.2O (165 mg, 3.92 mmol) at r.t, stirred overnight at r.t,
acidified to pH=3-4; extracted with EA, dried and concentrated to
give the title compound (278 mg, 100%). [M+H] Calc'd for
C.sub.18H.sub.11F.sub.2N.sub.3O.sub.3, 356; Found, 356.
Preparation 67B: tert-butyl
N-[(3R)-1-[2-(4-Cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)imidazo-
le-4-carbonyl]piperidin-3-yl]carbamate
##STR00428##
A mixture of
2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)imidazole-4-carbox-
ylic acid (300 mg, 0.78 mmol), N-((3R)(3-piperidyl))(tert-butoxy)
carboxamide (157 mg, 0.78 mmol), HATU (327 mg, 0.86 mmol) and NMM
(158 mg, 1.566 mmol) in DMF (5 mL) was stirred for 1 hr at r.t.
LC/MS showed the reaction was completed, concentrated to afford the
title compound (420 mg, 100%). [M+H] Calc'd for
C.sub.28H.sub.29F.sub.2N.sub.5O.sub.4, 538; Found, 538.
Example 67:
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5-fluoro-1-(3-fluoro-4-methoxyph-
enyl)imidazol-2-yl]-2-fluorobenzonitrile
##STR00429##
To a solution of tert-butyl
N-[(3R)-1-[2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)imidazo-
le-4-carbonyl]piperidin-3-yl]carbamate (420 mg, 0.78 mmol) in ACN
(10 mL) was added selectfluor (554 mg, 1.566 mmol) and 0.5 mL AcOH
was stirred for overnight at 90.degree. C., concentrated and
purified by prep-HPLC to afford the title compound (17 mg, 4.7%).
.sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.98-2.30 (3H, m),
2.40-2.42 (1H, m), 3.53-3.55 (3H, m), 4.20 (3H, s), 4.62-4.73 (2H,
m), 7.43-7.59 (5H, m), 7.91-7.94 (1H, m). [M+H] Calc'd for
C.sub.23H.sub.20F.sub.3N.sub.5O.sub.2, 456; Found, 456.
Example 68:
2-Fluoro-4-[5-fluoro-1-(3-fluoro-4-methoxyphenyl)-4-[(3S)-3-(methylamino)-
pyrrolidine-1-carbonyl]imidazol-2-yl]benzonitrile
##STR00430##
A solution of tert-butyl
N-[(3S)-1-[2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)imidazo-
le-4-carbonyl]pyrrolidin-3-yl]-N-methylcarbamate (400 mg, 0.74
mmol) in ACN (10 mL) was added selectflour (528 mg, 1.49 mmol) and
0.5 mL AcOH, which was stirred overnight at 90.degree. C. It was
then concentrated and purified by prep-HPLC to afford the title
compound (11 mg, 3%). .sup.1H NMR (400 MHz, DMSO-d6): .delta.
2.00-2.30 (2H, m), 2.63 (3H, d, J=5.6 Hz), 3.55-4.29 (5H, m), 3.94
(3H, s), 7.20-7.21 (1H, m), 7.25-7.30 (1H, m), 7.38-7.39 (2H, m),
7.66-7.69 (1H, m), 7.90-7.91 (1H, m), 8.75-8.94 (2H, m). [M+H]
Calc'd for C.sub.23H.sub.20F.sub.3N.sub.5O.sub.2, 456; Found,
456.
Example 69:
2-Fluoro-4-[1-(4-methoxyphenyl)-5-methyl-4-[(3S)-(3-ethylamino)pyrrolidin-
e-1-carbonyl]imidazol-2-yl]benzonitrile
##STR00431##
The title compound was prepared as TFA salt in 4% overall yield
according to the general procedure for the preparation of Example
12. 1H NMR (300 MHz, CD.sub.3OD): .delta. 2.30-2.32 (1H, m), 2.31
(3H, s), 2.47-2.48 (1H, m), 2.81 (3H, s), 3.88-4.39 (5H, m), 3.92
(3H, s), 7.11-7.14 (2H, m), 7.34-7.48 (3H, m), 7.46 (1H, d. J=9.9
Hz), 7.73 (1H, t, J=7.2 Hz). [M+H] Calc'd for
C.sub.24H.sub.24FN.sub.5O.sub.2, 434; Found, 434.
Example 70:
2-Fluoro-4-[1-(4-methoxyphenyl)-5-methyl-4-[(3R)-3-(methylamino)piperidin-
e-1-carbonyl]imidazol-2-yl]benzonitrile
##STR00432##
The title compound was prepared as TFA salt in 2% overall yield
according to the general procedure for the preparation of Example
12. .sup.1H NMR (300 MHz, CD.sub.3OD): .delta. 1.74-2.02 (3H, m),
2.26 (3H, s), 2.26-2.27 (1H, m), 2.79 (3H, s), 3.30-3.31 (2H, m),
3.67-3.74 (1H, m), 3.86 (3H, s), 3.97-4.08 (2H, m), 7.11-7.14 (2H,
m), 7.41-7.45 (4H, m), 7.79-7.81 (1H, m). [M+H] Calc'd for
C.sub.25H.sub.26FN.sub.5O.sub.2, 448; Found, 448.
Example 71:
2-Fluoro-4-[1-(4-methoxyphenyl)-4-[(3S)-3-(methylamino)pyrrolidine-1-carb-
onyl]imidazol-2-yl]benzonitrile
##STR00433##
The title compound was prepared as TFA salt in 6% overall yield
according to the general procedure for the preparation of Example
12 using ethyl bromopyruvate. .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 2.44-2.64 (2H, m), 2.84 (3H, s), 3.96 (3H, m), 3.85-4.38
(5H, m), 7.10-7.13 (2H, m), 7.48-7.52 (3H, m), 7.62-7.65 (1H, m),
7.93 (1H, t, J=7.2 Hz), 8.50 (1H, s). [M+H] Calc'd for
C.sub.23H.sub.22FN.sub.5O.sub.2, 420; Found, 420.
Example 72:
2-Fluoro-4-[1-(4-methoxyphenyl)-4-[(3R)-3-(methylamino)piperidine-1-carbo-
nyl]imidazol-2-yl]benzonitrile
##STR00434##
The title compound was prepared as TFA salt in 6% overall yield
according to the general procedure for the preparation of Example
12 using ethyl bromopyruvate. .sup.1H NMR (300 MHz, CD.sub.3OD):
.delta. 1.70-2.27 (4H, m), 2.80 (3H, s), 2.30-2.43 (3H, m), 3.85
(3H, s), 3.85-4.13 (2H, m), 7.06-7.08 (2H, m), 7.41-7.45 (3H, m),
7.55 (1H, d, J=9.9 Hz), 7.84 (1H, t, J=7.2 Hz), 8.27 (1H, s). [M+H]
Calc'd for C.sub.24H.sub.24FN.sub.5O.sub.2, 434; Found, 434.
Example 73:
2-Fluoro-4-[5-fluoro-1-(4-methoxyphenyl)-4-[(3S)-3-(methylamino)pyrrolidi-
ne-1-carbonyl]imidazol-2-yl]benzonitrile
##STR00435##
The title compound was prepared as TFA salt in 0.1% overall yield
according to the general procedure for the preparation of Example
58. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.74-2.15 (2H, m),
2.33 (3H, d, J=5.2 Hz), 3.20-4.23 (5H, m), 3.89 (3H, s), 7.02-7.04
(2H, m), 7.20-7.32 (4H, m), 7.56 (1H, t, J=7.2 Hz). [M+H] Calc'd
for C.sub.23H.sub.21F.sub.2N.sub.5O.sub.2, 438; Found, 438.
Example 74:
2-Fluoro-4-[5-fluoro-1-(4-methoxyphenyl)-4-[(3R)-3-(methylamino)piperidin-
e-1-carbonyl]imidazol-2-yl]benzonitrile
##STR00436##
The title compound was prepared as TFA salt in 0.5% overall yield
according to the general procedure for the preparation of Example
68. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.68-2.18 (4H, m),
2.63 (3H, s), 2.99-3.02 (1H, m), 3.54-3.70 (2H, m), 3.87 (3H, s),
3.87-4.48 (2H, m), 7.11-7.14 (2H, m), 7.30-7.37 (4H, m), 7.68 (1H,
t, J=7.6 Hz). [M+H] Calc'd for
C.sub.24H.sub.23F.sub.2N.sub.5O.sub.2, 452; Found, 452.
Example 75:
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5-chloro-1-(2-methylindazol-5-yl-
)imidazol-2-yl]-2-fluorobenzonitrile
##STR00437##
The title compound was prepared as the formic acid salt in 0.4%
overall yield according to the general procedure for the
preparation of Example 66. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.43 (2H, m), 1.78 (1H, m), 1.95 (1H, m), 3.01 (1H, m),
4.25 (3H, s), 4.44 (1H, br s), 4.81 (1H, br s), 7.19 (1H, d, J=8.7
Hz), 7.25 (1H, d, J=8.4 Hz), 7.50 (1H, br s), 7.75 (1H, d, J=9 Hz),
7.84 (1H, t, J=7.4 Hz), 7.86 (1H, s), 8.05 (1H, s), 8.26 (1H, br
s). [M+H] Calc'd for C.sub.24H.sub.21ClFN.sub.7O, 478; Found,
478.
Preparation 76A: Ethyl
5-chloro-1-(3-chloro-2-methylindazol-5-yl)-2-(4-cyano-3-fluorophenyl)imid-
azole-4-carboxylate
##STR00438##
To a solution of ethyl
2-(4-cyano-3-fluorophenyl)-1-(2-methylindazol-5-yl)imidazole-4-carboxylat-
e (800 mg, 2.06 mmol) in ACN/AcOH (10/1 mL) was added NCS (550 mg,
4.12 mmol) at r.t. The mixture was stirred overnight at 50.degree.
C. H.sub.2O was added and extracted with DCM, dried, concentrated
and purified by flash chromatography on silica gel (PE/EA=2/1) to
afford the title compound (140 mg, 15%). .sup.1H NMR (400 MHz,
CDCl.sub.3): .delta. 1.45 (3H, t, J=7.2 Hz), 4.24 (3H, s), 4.49
(2H, q, J=7.2 Hz), 7.07-7.09 (1H, m), 7.26-7.29 (1H, m), 7.39-7.50
(3H, m), 7.82 (1H, d, J=9.2 Hz). [M+H] Calc'd for
C.sub.21H.sub.14C.sub.12FN.sub.5O.sub.2, 458; Found, 458.
Example 76:
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5-chloro-1-(3-chloro-2-methylind-
azol-5-yl)imidazol-2-yl]-2-fluorobenzonitrile
##STR00439##
The title compound was prepared as TFA salt in 3% overall yield
according to the procedure for the preparation of example 53
starting from ethyl
2-(4-cyano-3-fluorophenyl)-1-(2-methylindazol-5-yl)imidazole-4-carboxylat-
e. .sup.1H NMR (400 MHz, CD.sub.3OD): .delta. 1.77-1.81 (2H, m),
1.95-1.96 (1H, m), 2.20-2.21 (1H, m), 3.34-3.69 (3H, m), 4.20-4.22
(4H, m), 4.46-4.69 (1H, m), 7.27-7.33 (2H, m), 7.40-7.46 (1H, m),
7.61-7.65 (1H, m), 7.79-7.81 (2H, m). [M+H] Calc'd for
C.sub.24H.sub.20C.sub.12FN.sub.7O, 512; Found, 512.
Example 77:
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5-fluoro-1-(2-methylindazol-5-yl-
)imidazol-2-yl]-2-fluorobenzonitrile
##STR00440##
The title compound was prepared as the formic acid salt in 0.1%
overall yield according to the general procedure for the
preparation of Example 58. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.28 (2H, m), 1.75 (1H, m), 1.89 (1H, m), 3.01 (1H, m),
4.25 (3H, s), 4.24 (1H, br s), 6.65 (1H, br s), 7.16 (1H, dd, J=2
and 8.9 Hz), 7.27 (1H, d, J=9.7 Hz), 7.50 (1H, br s), 7.60 (1H, d,
J=8.6 Hz), 7.85 (1H, t, J=7.8 Hz), 7.89 (1H, s), 7.98 (1H, s), 8.36
(1H, br s). [M+H] Calc'd for C.sub.24H.sub.21F.sub.2N.sub.7O, 462;
Found, 462.
Example 78:
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-1-(6-cyclopropylpyridin-3-yl)-5--
methylimidazol-2-yl]-2-fluorobenzonitrile
##STR00441##
The title compound was prepared as formic acid salt in 2% overall
yield according to the general procedure for the preparation of
Example 12 using 6-cyclopropylpyridin-3-amine. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 0.99 (2H, s), 1.16 (2H, d, J=6.3 Hz),
1.49 (2H, m), 1.75 (1H, m), 1.97 (1H, m), 2.17 (3H, s), 2.24 (1H,
m), 2.92 (2H, m), 3.07 (2H, m), 4.14 (1H, m), 4.50 (1H, m), 7.16
(1H, d, J=7.7 Hz), 7.36 (1H, m), 7.52 (1H, d, J=8.2 Hz), 7.80 (1H,
d, J=6.4 Hz), 7.87 (1H, t, J=8.0 Hz), 8.43 (1H, br s). [M+H] Calc'd
for C.sub.25H.sub.25FN.sub.6O, 445; Found, 445.
Example 79:
4-[4-[(3S)-3-Aminopyrrolidine-1-carbonyl]-1-(6-cyclopropylpyridin-3-yl)-5-
-methylimidazol-2-yl]-2-fluorobenzonitrile
##STR00442##
The title compound was prepared as formic acid salt in 0.8% overall
yield according to the general procedure for the preparation of
Example 12 using 6-cyclopropylpyridin-3-amine. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 0.99 (2H, s), 1.05 (2H, d, J=10.1 Hz),
1.76 (1H, m), 1.85 (1H, m), 2.12 (1H, m), 2.22 (3H, s), 3.37 (1H,
m), 3.56 (1H, m), 3.66 (1H, m), 3.85 (1H, m), 4.06-4.15 (1H, m),
7.16 (1H, t, J=8.8 Hz), 7.38 (1H, d, J=10.7 Hz), 7.53 (1H, d, J=8.3
Hz), 7.79 (1H, d, J=5.8 Hz), 7.86 (1H, m), 8.44 (1H, br s). [M+H]
Calc'd for C.sub.24H.sub.23FN.sub.6O, 431; Found, 431.
Example 80:
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5-chloro-1-(6-cyclopropylpyridin-
-3-yl)imidazol-2-yl]-2-fluorobenzonitrile
##STR00443##
The title compound was prepared as formic acid salt in 4% overall
yield according to the general procedure for the preparation of
Example 66 using 6-cyclopropylpyridin-3-amine. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 0.99 (2H, s), 1.12 (2H, s), 1.52 (2H,
m), 1.82 (1H, m), 1.99 (1H, m), 2.24 (1H, m), 2.92 (1H, m), 3.17
(2H, m), 4.12 (1H, m), 4.25 (1H, m), 4.45 (1H, m), 7.21 (1H, d,
J=8.0 Hz), 7.43 (1H, m), 7.55 (1H, d, J=8.2 Hz), 7.85 (1H, m), 7.94
(1H, t, J=6.8 Hz), 8.48 (1H, br s). [M+H] Calc'd for
C.sub.24H.sub.22ClFN.sub.6O, 465; Found, 465.
Example 81:
4-[4-[(3S)-3-Aminopyrrolidine-1-carbonyl]-5-chloro-1-(6-cyclopropylpyridi-
n-3-yl)imidazol-2-yl]-2-fluorobenzonitrile
##STR00444##
The title compound was prepared as formic acid salt in 3% overall
yield according to the general procedure for the preparation of
Example 66 using 6-cyclopropylpyridin-3-amine. 1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 0.99 (2H, s), 2.03 (1H, m), 2.22 (3H, m),
3.65 (1H, m), 3.68 (1H, m), 3.73 (1H, m), 3.88 (1H, m), 4.11 (1H,
m), 4.25 (1H, m), 7.20 (1H, d, J=6.9 Hz), 7.46 (1H, d, J=10.4 HJz),
7.56 (1H, d, J=8.0 Hz), 7.85 (1H, m), 7.93 (1H, m), 8.49 (1H, br
s). [M+H] Calc'd for C.sub.23H.sub.20ClFN.sub.6O, 451; Found,
451.
Example 82:
2-(4-Cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)-5-methyl-N-[(3R)--
pyrrolidin-3-yl]imidazole-4-carboxamide
##STR00445##
The title compound was prepared as formic acid salt in 2% overall
yield according to the general procedure for the preparation of
Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.98-2.05
(1H, m), 2.18-2.26 (1H, m), 2.32 (3H, s), 3.17-3.22 (2H, m),
3.36-3.42 (2H, m), 3.92 (3H, s), 4.58-4.64 (1H, m), 7.18 (1H, dd,
J=1.5 and 8.2 Hz), 7.25 (1H, dd, J=1.5 and 8.7 Hz), 7.35 (1H, t,
J=8.9 Hz), 7.54 (1H, dd, J=2.4 and 11.5 Hz), 7.58 (1H, dd, J=1.3
and 8.0 Hz), 7.88 (1H, t, J=7.0 Hz), 8.45 (1H, d, J=7.6 Hz), 9.09
(1H, br s). [M+H] Calc'd for C.sub.23H.sub.21F.sub.2N.sub.5O.sub.2,
438; Found, 438.
Example 83:
2-(4-Cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)-5-methyl-N-[(3S)--
pyrrolidin-3-yl]imidazole-4-carboxamide
##STR00446##
The title compound was prepared as formic acid salt in 5% overall
yield according to the general procedure for the preparation of
Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.99-2.07
(1H, m), 2.19-2.24 (1H, m), 2.32 (3H, s), 3.20 (2H, m), 3.38 (2H,
m), 3.92 (3H, s), 4.61 (1H, m), 7.19 (1H, d, J=8.2 Hz), 7.24 (1H,
d, J=8.7 Hz), 7.35 (1H, t, J=8.8 Hz), 7.57 (2H, t, J=11.2 Hz), 7.87
(1H, t, J=6.8 Hz), 8.47 (1H, d, J=7.3 Hz), 9.16 (1H, br s). [M+H]
Calc'd for C.sub.23H.sub.21F.sub.2N.sub.5O.sub.2, 438; Found,
438.
Example 84:
5-Chloro-2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)-N-[(3R)--
piperidin-3-yl]imidazole-4-carboxamide
##STR00447##
The title compound was prepared as formic acid salt in 4% overall
yield according to the general procedure for the preparation of
Example 66. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.56-1.65
(2H, m), 1.74-1.81 (2H, m), 2.64 (1H, t, J=10.6 Hz), 2.75 (1H, t,
J=10.7 Hz), 2.98 (1H, d, J=11.8 Hz), 3.08 (1H, d, J=11.6 Hz), 3.93
(3H, s), 4.06 (1H, m), 7.23 (1H, d, J=8.0 Hz), 7.37 (1H, m), 7.60
(2H, d, J=10.4 Hz), 7.89 (1H, t, J=7.6 Hz), 8.23 (1H, d, J=8.6 Hz),
8.29 (1H, s). [M+H] Calc'd for
C.sub.23H.sub.20ClF.sub.2N.sub.5O.sub.2, 472; Found, 472.
Example 85:
5-Chloro-2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)-N-[(3S)--
piperidin-3-yl]imidazole-4-carboxamide
##STR00448##
The title compound was prepared as formic acid salt in 3% overall
yield according to the general procedure for the preparation of
Example 66. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.55-1.61
(2H, m), 1.64-1.81 (2H, m), 2.60 (1H, t, J=12.1 Hz), 2.69 (1H, t,
J=9.8 Hz), 2.93 (1H, d, J=10.8 Hz), 3.03 (1H, d, J=11.1 Hz), 3.93
(3H, s), 4.00 (1H, m), 7.23 (1H, d, J=8.3 Hz), 7.35 (1H, m), 7.60
(2H, m), 7.91 (1H, t, J=7.1 Hz), 8.16 (1H, d, J=8.5 Hz), 8.23 (1H,
s). [M+H] Calc'd for C23H20ClF2N5O2, 472; Found, 472.
Example 86:
2-(4-Cyano-3-fluorophenyl)-5-fluoro-1-(3-fluoro-4-methoxyphenyl)-N-[(3R)--
piperidin-3-yl]imidazole-4-carboxamide
##STR00449##
The title compound was prepared as formic acid salt in 4% overall
yield according to the general procedure for the preparation of
Example 68. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.09 (2H,
m), 1.23 (1H, m), 1.44 (1H, m), 1.76 (1H, m), 2.76 (1H, m), 2.93
(1H, m), 3.92 (3H, s), 6.27 (1H, s), 7.21 (1H, m), 7.39 (1H, m),
7.58 (2H, m), 7.91 (1H, m), 8.38 (1H, m). [M+H] Calc'd for
C.sub.23H.sub.20F.sub.3N.sub.5O.sub.2, 456; Found, 456.
Example 87:
2-(4-Cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)-5-methyl-N-piperi-
din-4-ylimidazole-4-carboxamide
##STR00450##
The title compound was prepared as formic acid salt in 2% overall
yield according to the general procedure for the preparation of
Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.63-1.68
(1H, m), 1.82 (1H, m), 2.31 (3H, s), 2.73 (1H, t, J=11.1 Hz), 3.14
(1H, d, J=11.7 Hz), 3.92 (3H, s), 7.18 (1H, dd, J=1.4 and 8.2 Hz),
7.34 (1H, t, J=8.9 Hz), 7.59 (1H, dd, J=2.4 and 11.6 Hz), 7.59 (1H,
dd, J=1.4 and 10.9 Hz), 7.87 (1H, t, J=6.6 Hz), 7.95 (1H, d, J=8.2
Hz), 8.27 (1H, br s), 8.34 (1H, br s). [M+H] Calc'd for
C.sub.24H.sub.23F.sub.2N.sub.5O.sub.2, 452; Found, 452.
Example 88:
4-[4-[3-(Aminomethyl)azetidine-1-carbonyl]-1-(3-fluoro-4-methoxyphenyl)-5-
-methylimidazol-2-yl]-2-fluorobenzonitrile
##STR00451##
The title compound was prepared as formic acid salt in 0.9% overall
yield according to the general procedure for the preparation of
Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 2.35 (3H,
s), 2.72 (1H, m), 2.91 (2H, m), 3.75 (1H, m), 3.91 (3H, s), 4.06
(1H, t, J=9.6 Hz), 4.36 (1H, m), 4.66 (1H, t, J=9.1 Hz), 7.17 (1H,
dd, J=1.4 and 8.3 Hz), 7.23 (1H, d, J=7.5 Hz), 7.35 (2H, t, J=8.9
Hz), 7.40 (1H, d, J=10.8 Hz), 7.54 (1H, dd, J=2.4 and 11.6 Hz),
7.85 (1H, t, J=7.8 Hz), 8.32 (1H, br s). [M+H] Calc'd for
C.sub.23H.sub.21F.sub.2N.sub.5O.sub.2, 438; Found, 438.
Example 89:
4-[4-[(3S)-3-Aminopyrrolidine-1-carbonyl]-5-fluoro-1-(3-fluoro-4-methoxyp-
henyl)imidazol-2-yl]-2-fluorobenzonitrile
##STR00452##
The title compound was prepared as formic acid salt in 0.1% overall
yield according to the general procedure for the preparation of
Example 68. Calc'd for C.sub.22H18F.sub.3N.sub.5O.sub.2, 442;
Found, 442.
Example 90:
4-[4-(1,7-Diazaspiro[4.4]nonane-7-carbonyl)-5-methyl-1-(2-methylindazol-5-
-yl)imidazol-2-yl]-2-fluorobenzonitrile
##STR00453##
The title compound was prepared as the formic acid salt in 1%
overall yield according to the general procedure for the
preparation of Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.77-1.92 (6H, m), 2.27 (3H, s), 2.95 (2H, m), 3.73 (1H,
m), 3.99 (1H, m), 4.14 (1H, m), 4.23 (3H, s), 7.20 (2H, m), 7.37
(1H, m), 7.83 (3H, m), 8.18 (1H, m), 8.50 (1H, m). [M+H] Calc'd for
C.sub.27H.sub.26FN.sub.7O, 484; Found, 484.
Example 91:
4-[4-(2,6-Diazaspiro[3.4]octane-6-carbonyl)-5-methyl-1-(2-methylindazol-5-
-yl)imidazol-2-yl]-2-fluorobenzonitrile
##STR00454##
The title compound was prepared as the formic acid salt in 2.3%
overall yield according to the general procedure for the
preparation of Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 2.06-2.22 (2H, m), 2.26 (3H, s), 2.32 (1H, m), 2.42 (1H,
m), 3.51-3.58 (2H, m), 4.06 (1H, m), 4.14 (1H, m), 4.23 (3H, s),
7.22 (2H, m), 7.39 (1H, t, J=11.2 Hz), 7.76-7.85 (3H, m), 8.29 (1H,
s), 8.49 (1H, s). [M+H] Calc'd for C.sub.26H.sub.24FN.sub.7O, 470;
Found, 470.
Example 92:
4-[4-(1,7-Diazaspiro[3.4]octane-7-carbonyl)-5-methyl-1-(1-methylindazol-5-
-yl)imidazol-2-yl]-2-fluorobenzonitrile
##STR00455##
The title compound was prepared as the formic acid salt in 0.2%
overall yield according to the general procedure for the
preparation of Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.15 (1H, m), 2.06-2.22 (2H, m), 2.26 (3H, s), 2.60 (1H,
m), 3.51-3.58 (2H, m), 4.06 (1H, m), 4.14 (1H, m), 4.23 (3H, s),
7.22 (2H, m), 7.39 (1H, t, J=11.2 Hz), 7.76-7.85 (3H, m), 8.29 (1H,
s), 8.49 (1H, s). [M+H] Calc'd for C.sub.26H.sub.24FN.sub.7O, 470;
Found, 470.
Example 93:
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-(1,7-diazaspiro[3.4]octane-7-carbo-
nyl) imidazol-2-yl]-2-fluorobenzonitrile
##STR00456##
The title compound was prepared as the formic acid salt in 0.8%
overall yield according to the general procedure for the
preparation of Example 57. .sup.1H NMR (400 MHz, DMSO-d6): .delta.
1.14 (1H, m), 2.22 (2H, m), 2.67 (1H, m), 3.69 (1H, m), 3.89 (2H,
m), 4.14 (1H, m), 4.22 (3H, s), 4.39 (1H, m), 7.16 (1H, d, J=10.6
Hz), 7.26 (1H, t, J=7.5 Hz), 7.75 (1H, d, J=9.0 Hz), 7.85 (2H, m),
8.16 (1H, s). [M+H] Calc'd for C.sub.25H.sub.21ClFN.sub.7O, 490;
Found, 490.
Example 94:
4-[4-[(3S)-3-(Dimethylamino)pyrrolidine-1-carbonyl]-5-methyl-1-(2-methyli-
ndazol-5-yl) imidazol-2-yl]-2-fluorobenzonitrile
##STR00457##
The title compound was prepared as the formic acid salt in 3%
overall yield according to the general procedure for the
preparation of Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.71-1.79 (1H, m), 1.99-2.13 (1H, m), 2.21 (3H, s), 2.26
(3H, s), 2.67-2.74 (1H, m), 3.21-3.26 (1H, m), 3.46 (1H, m),
3.68-3.79 (2H, m), 3.94 (1H, m), 4.23 (3H, s), 4.23 (1H, m), 7.22
(1H, m), 7.35 (1H, dd, J=1.4 and 11.2 Hz), 7.76-7.85 (2H, m), 8.47
(1H, s). [M+H] Calc'd for C.sub.26H.sub.26FN.sub.7O, 472; Found,
472.
Example 95:
4-[4-[(3S)-3-(Dimethylamino)pyrrolidine-1-carbonyl]-5-methyl-1-(1-methyli-
ndazol-5-yl)imidazol-2-yl]-2-fluorobenzonitrile
##STR00458##
The title compound was prepared as the formic acid salt in 3.5%
overall yield according to the general procedure for the
preparation of Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.71-1.78 (1H, m), 2.06-2.11 (1H, m), 2.21 (3H, s), 2.25
(3H, s), 2.43 (1H, m), 3.68 (1H, m), 3.94 (1H, m), 4.24 (3H, s),
4.27 (1H, m), 7.08 (1H, m), 7.16 (1H, m), 7.31-7.41 (2H, m), 7.76
(1H, m), 7.86 (2H, m), 8.17 (1H, s). [M+H] Calc'd for
C.sub.26H.sub.26FN.sub.7O, 472; Found, 472.
Example 96:
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-[(3S)-3-(dimethylamino)pyrrolidine-
-1-carbonyl]-5-methylimidazol-2-yl]-2-fluorobenzonitrile
##STR00459##
The title compound was prepared as formic acid salt in 11% overall
yield according to the procedure for the preparation of example 53.
.sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta. 1.79-1.92 (2H, m), 2.13
(1H, m), 2.26 (3H, s), 3.45-3.48 (1H, m), 3.68 (1H, m), 3.83 (1H,
m), 3.93 (1H, m), 4.19 (3H, s), 4.26 (1H, m), 7.19-7.29 (2H, m),
7.39-7.44 (1H, m), 7.79-7.85 (3H, m). [M+H] Calc'd for
C.sub.26H.sub.25ClFN.sub.7O, 506; Found, 506.
Example 97:
2-Fluoro-4-[5-methyl-4-[(3S)-3-(methylamino)piperidine-1-carbonyl]-1-(2-m-
ethylindazol-5-yl)imidazol-2-yl]benzonitrile
##STR00460##
The title compound was prepared as formic acid salt in 2.5% overall
yield according to the general procedure for the preparation of
Example 12. .sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta. 1.39-1.48
(2H, m), 1.76-1.78 (1H, m), 1.98 (1H, m), 2.17 (3H, s), 2.36 (3H,
d, J=22.6 Hz), 2.66 (1H, m), 2.99-3.13 (2H, m), 4.15 (1H, m), 4.25
(3H, s), 4.40 (1H, m), 4.63 (1H, m), 7.20 (2H, d, J=8.0 Hz), 7.38
(1H, m), 7.78 (2H, t, J=9.6 Hz), 7.86 (1H, s), 8.24 (1H, s), 8.49
(1H, s). [M+H] Calc'd for C.sub.26H.sub.26FN.sub.7O, 472; Found,
472.
Example 98:
2-Fluoro-4-[5-methyl-4-[(3R)-3-(methylamino)piperidine-1-carbonyl]-1-(2-m-
ethylindazol-5-yl)imidazol-2-yl]benzonitrile
##STR00461##
The title compound was prepared as formic acid salt in 2% overall
yield according to the general procedure for the preparation of
Example 12. .sup.1HNMR (400 MHz, DMSO-d.sub.6): .delta. 1.47 (2H,
m), 1.79 (1H, m), 2.05 (1H, m), 2.18 (3H, s), 2.44 (3H, d, J=17.2
Hz), 2.76 (2H, m), 3.04 (1H, m), 4.14 (1H, m), 4.22 (3H, s), 4.41
(1H, m), 4.65 (1H, m), 7.21 (2H, d, J=8.3 Hz), 7.38 (1H, m), 7.78
(2H, t, J=9.1 Hz), 7.86 (1H, s), 8.20 (1H, br s), 8.48 (1H, s).
[M+H] Calc'd for C.sub.26H.sub.26FN.sub.7O, 472; Found, 472.
Example 99:
4-[4-[(3S)-3-(Dimethylamino)pyrrolidine-1-carbonyl]-1-(2-methylindazol-5--
yl) imidazol-2-yl]-2-fluorobenzonitrile
##STR00462##
The title compound was prepared as the formic acid salt in 0.5%
overall yield according to the general procedure for the
preparation of Example 12. [M+H] Calc'd for
C.sub.25H.sub.24FN.sub.7O, 458; Found, 458.
Example 100:
4-[5-Chloro-4-[(3S)-3-(dimethylamino)pyrrolidine-1-carbonyl]-1-(2-methyli-
ndazol-5-yl) imidazol-2-yl]-2-fluorobenzonitrile
##STR00463##
The title compound was prepared as the formic acid salt in 9% yield
starting from
4-[4-[(3S)-3-(dimethylamino)pyrrolidine-1-carbonyl]-1-(2-methylindazol-5--
yl)imidazol-2-yl]-2-fluorobenzonitrile using NCS. .sup.1HNMR (400
MHz, DMSO-d.sub.6): .delta. 1.68-1.83 (1H, m), 2.13 (1H, m), 2.20
(6H, s), 2.67-2.75 (1H, m), 3.67-3.80 (2H, m), 3.94 (1H, m), 4.20
(3H, s), 4.32 (1H, m), 7.20 (1H, m), 7.27 (1H, t, J=6.6 Hz), 7.48
(1H, t, J=11.1 Hz), 7.73 (1H, d, J=9.4 Hz), 7.84 (1H, s), 7.87 (1H,
s), 8.10 (1H, s), 8.45 (1H, br s). [M+H] Calc'd for
C.sub.25H.sub.23ClFN.sub.7O, 492; Found, 492.
Example 101:
4-[5-Chloro-1-(3-chloro-2-methylindazol-5-yl)-4-[(3S)-3-(dimethylamino)py-
rrolidine-1-carbonyl]imidazol-2-yl]-2-fluorobenzonitrile
##STR00464##
The title compound was prepared as the formic acid salt in 10%
yield starting from
4-[4-[(3S)-3-(dimethylamino)pyrrolidine-1-carbonyl]-1-(2-methylindazol-5--
yl)imidazol-2-yl]-2-fluorobenzonitrile with excess of NCS. [M+H]
Calc'd for C.sub.25H.sub.22Cl.sub.2FN.sub.7O, 526; Found, 526.
Example 102:
4-[4-[(3S)-3-(Dimethylamino)pyrrolidine-1-carbonyl]-1-(2,3-dimethylindazo-
l-5-yl)-5-methylimidazol-2-yl]-2-fluorobenzonitrile
##STR00465##
The title compound was prepared as the formic acid salt in 0.6%
overall yield according to the general procedure for the
preparation of Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.95-2.07 (1H, m), 2.25 (1H, m), 2.26 (3H, s), 2.69 (3H,
s), 3.32 (3H, s), 3.51 (2H, m), 3.57 (1H, m), 3.88 (1H, m), 4.02
(3H, s), 4.37 (1H, m), 7.01-7.09 (1H, m), 7.25 (1H, m), 7.41 (1H,
d, J=10.8 Hz), 7.71 (1H, d, J=8.6 Hz), 7.79 (1H, m), 7.86 (1H, s),
8.14 (1H, s). [M+H] Calc'd for C.sub.27H.sub.28FN.sub.7O, 486;
Found, 486.
Example 103:
4-[1-(2,3-Dimethylindazol-5-yl)-5-methyl-4-[(3S)-3-(methylamino)pyrrolidi-
ne-1-carbonyl]imidazol-2-yl]-2-fluorobenzonitrile
##STR00466##
The title compound was prepared as the formic acid salt in 1.7%
overall yield according to the general procedure for the
preparation of Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.81 (1H, m), 1.90 (1H, m), 2.03-2.08 (1H, m), 2.26 (3H,
s), 2.39 (3H, d, J=7.6 Hz), 2.61 (3H, s), 3.34-3.70 (4H, m), 3.93
(1H, m), 4.13 (3H, s), 4.16 (1H, m), 7.14 (1H, d, J=8.5 Hz), 7.24
(1H, m), 7.41 (1H, m), 7.70 (1H, d, J=8.9 Hz), 7.79 (1H, m), 7.88
(1H, s), 8.19 (1H, s). [M+H] Calc'd for C.sub.26H.sub.26FN.sub.7O,
472; Found, 472.
Example 104:
2-(4-Cyano-3-fluorophenyl)-1-(2,3-dimethylindazol-5-yl)-5-methyl-N-[(3R)--
piperidin-3-yl]imidazole-4-carboxamide
##STR00467##
The title compound was prepared as the formic acid salt in 0.2%
overall yield according to the general procedure for the
preparation of Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.58-1.68 (2H, m), 1.84 (2H, m), 2.32 (3H, s), 2.60 (3H,
s), 2.67 (1H, m), 2.81 (1H, m), 3.04 (1H, m), 3.15 (1H, m), 4.10
(3H, s), 7.15 (1H, m), 7.21 (1H, d, J=8.4 Hz), 7.56 (1H, d, J=9.9
Hz), 7.70 (1H, d, J=9.7 Hz), 7.80 (1H, m), 7.87 (1H, s), 8.10 (1H,
d, J=7.9 Hz), 8.16 (1H, s). [M+H] Calc'd for
C.sub.26H.sub.26FN.sub.7O, 472; Found, 472.
Example 105:
4-[1-(2,3-Dimethylindazol-5-yl)-5-methyl-4-[(3R)-3-(methylamino)piperidin-
e-1-carbonyl]imidazol-2-yl]-2-fluorobenzonitrile
##STR00468##
The title compound was prepared as the formic acid salt in 0.6%
overall yield according to the general procedure for the
preparation of Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.55 (2H, m), 1.82 (1H, m), 2.08 (1H, m), 2.19 (3H, s),
2.59 (3H, s), 2.61 (3H, s), 3.05 (2H, m), 3.47 (1H, m), 4.10 (3H,
s), 4.42 (1H, m), 7.24 (1H, d, J=10.8 Hz), 7.37-7.48 (1H, m), 7.70
(1H, d, J=8.7 Hz), 7.79 (1H, t, J=6.6 Hz), 7.88 (1H, s), 8.15 (1H,
s). [M+H] Calc'd for C.sub.28H.sub.27FN.sub.7O, 486; Found,
486.
Example 106:
1-(3-Chloro-2-methylindazol-5-yl)-2-(4-cyano-3-fluorophenyl)-N-[(3R)-1-me-
thylpyrrolidin-3-yl]imidazole-4-carboxamide
##STR00469##
The title compound was prepared as the formic acid salt in 14%
overall yield according to the general procedure for the
preparation of Example 57. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
1.81 (1H, m), 2.21 (1H, m), 2.34 (3H, s), 2.57 (1H, d, J=9.9 Hz),
2.75 (2H, m), 4.18 (3H, s), 4.46 (1H, m), 7.20 (1H, d, J=9.2 Hz),
7.24 (1H, d, J=8.2 Hz), 7.62 (1H, d, J=10.7 Hz), 7.73 (1H, d, J=8.9
Hz), 7.83 (1H, d, J=7.8 Hz), 7.86 (1H, s), 8.10 (2H, s), 8.20 (1H,
s). [M+H] Calc'd for C.sub.24H.sub.21ClFN.sub.7O, 478; Found,
478.
Example 107:
1-(3-Chloro-2-methylindazol-5-yl)-2-(4-cyano-3-fluorophenyl)-N-[(3S)-1-me-
thylpyrrolidin-3-yl]imidazole-4-carboxamide
##STR00470##
The title compound was prepared as the formic acid salt in 14%
overall yield according to the general procedure for the
preparation of Example 57. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
1.87-1.94 (1H, m), 2.08-2.32 (1H, m), 2.51 (3H, s), 2.76 (1H, m),
2.83 (1H, m), 3.01 (2H, m), 4.17 (3H, s), 4.54 (1H, m), 7.20 (1H,
dd, J=2 and 9.1 Hz), 7.61 (1H, dd, J=1.1 and 10.6 Hz), 7.83 (1H,
s), 7.85 (1H, t, J=16.5 Hz), 8.13 (1H, s), 8.25 (1H, d, J=7.7 Hz).
[M+H] Calc'd for C.sub.24H.sub.21ClFN.sub.7O, 478; Found, 478.
Example 108:
2-(4-Cyano-3-fluorophenyl)-5-methyl-1-(2-methylindazol-5-yl)-N-[(3R)-1-me-
thylpyrrolidin-3-yl]imidazole-4-carboxamide
##STR00471##
The title compound was prepared as the formic acid salt in 3%
overall yield according to the general procedure for the
preparation of Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.78 (1H, m), 2.20 (1H, m), 2.29 (3H, s), 2.31 (3H, s),
2.37 (1H, m), 2.64-2.69 (2H, m), 4.23 (3H, s), 4.44 (1H, m), 7.19
(2H, m), 7.57 (1H, d, J=10.6 Hz), 7.77 (1H, d, J=11.1 Hz), 7.82
(1H, d, J=9.9 Hz), 7.85 (1H, s), 7.96 (1H, d, J=7.4 Hz), 8.22 (1H,
br s), 8.50 (1H, s). [M+H] Calc'd for C.sub.25H.sub.24FN.sub.7O,
458; Found, 458.
Example 109:
2-(4-Cyano-3-fluorophenyl)-5-methyl-1-(2-methylindazol-5-yl)-N-[(3S)-1-me-
thylpyrrolidin-3-yl]imidazole-4-carboxamide
##STR00472##
The title compound was prepared as the formic acid salt in 4%
overall yield according to the general procedure for the
preparation of Example 12. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.78 (1H, m), 2.19 (1H, m), 2.30 (6H, s), 2.41 (1H, m),
2.54 (1H, m), 2.68-2.73 (2H, m), 4.22 (3H, s), 4.44 (1H, m), 7.19
(2H, m), 7.57 (1H, d, J=10.8 Hz), 7.76 (1H, d, J=11.2 Hz), 7.80
(1H, d, J=9.7 Hz), 7.85 (1H, s), 7.99 (1H, d, J=7.9 Hz), 8.21 (1H,
br s), 8.50 (1H, s). [M+H] Calc'd for C.sub.25H.sub.24FN.sub.7O,
458; Found, 458.
Example 110:
4-[1-(3-Chloro-6-fluoro-2-methylindazol-5-yl)-4-[(3S)-3-(dimethylamino)py-
rrolidine-1-carbonyl]-5-methylimidazol-2-yl]-2-fluorobenzonitrile
##STR00473##
The title compound was prepared as formic acid salt in 9% yield by
treating Example 48 with 1 equiv. of NCS. [M+H] Calc'd for
C.sub.26H.sub.24ClF.sub.2N70, 510; Found, 510.
Example 111:
4-[1-(3-Chloro-6-fluoro-2-methylindazol-5-yl)-5-methyl-4-[(3S)-3-(methyla-
mino)pyrrolidine-1-carbonyl]imidazol-2-yl]-2-fluorobenzonitrile
##STR00474##
The title compound was prepared as formic acid salt in 15% yield by
treating Example 49 with 1 equiv. of NCS. [M+H] Calc'd for
C.sub.25H.sub.22ClF.sub.2N70, 524; Found, 524.
Example 112:
4-[1-(3-Chloro-6-fluoro-2-methylindazol-5-yl)-4-[(3S)-3-(dimethylamino)py-
rrolidine-1-carbonyl]-5-methylimidazol-2-yl]-2-fluorobenzonitrile
##STR00475##
The title compound was prepared as formic acid salt in 15% yield by
treating Example 51 with 1 equiv. of NCS. [M+H] Calc'd for
C.sub.25H.sub.22ClF.sub.2N70, 524; Found, 524.
Example 113:
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-[(3S)-3-(methylamino)pyrrolidine-1-
-carbonyl]imidazol-2-yl]-2-fluorobenzonitrile
##STR00476##
The title compound was prepared as the formic acid salt in 6%
overall yield according to the general procedure for the
preparation of Example 57. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
2.08-2.39 (3H, m), 2.66 (3H, s), 3.61 (1H, m), 3.72 (1H, m), 3.83
(1H, m), 4.19 (3H, s), 4.31 (1H, m), 7.19 (1H, d, J=9.0 Hz), 7.24
(1H, br s), 7.54 (1H, d, J=11.2 Hz), 7.75 (1H, d, J=9.2 Hz), 7.84
(1H, s), 7.87 (1H, s), 8.17 (1H, s), 8.72 (1H, br s). [M+H] Calc'd
for C.sub.24H.sub.21ClFN.sub.7O, 478; Found, 478.
Example 114:
1-(3-Chloro-2-methylindazol-5-yl)-2-(4-cyano-3-fluorophenyl)-N-[(3R)-pipe-
ridin-3-yl]imidazole-4-carboxamide
##STR00477##
The title compound was prepared as the formic acid salt in 4.6%
overall yield according to the general procedure for the
preparation of Example 57. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
1.70 (2H, m), 1.89 (2H, m), 2.74 (1H, m), 2.94 (1H, m), 3.23 (2H,
m), 4.19 (3H, s), 4.20 (1H, m), 7.20 (1H, d, J=9.1 Hz), 7.24 (1H,
d, J=8.0 Hz), 7.60 (1H, d, J=10.4 Hz), 7.74 (1H, d, J=8.6 Hz), 7.85
(1H, s), 7.86 (1H, s), 8.15 (1H, s), 8.34 (1H, d, J=8.0 Hz), 8.65
(1H, br s). [M+H] Calc'd for C.sub.24H.sub.21ClFN.sub.7O, 478;
Found, 478.
Example 115:
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-[(3R)-3-(methylamino)piperidine-1--
carbonyl]imidazol-2-yl]-2-fluorobenzonitrile
##STR00478##
The title compound was prepared as the formic acid salt in 6%
overall yield according to the general procedure for the
preparation of Example 57. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
1.56 (1H, m), 1.68 (1H, m), 1.83 (1H, m), 2.11 (1H, m), 2.66 (3H,
s), 3.25 (1H, m), 3.32 (2H, s), 4.19 (3H, s), 7.19 (1H, d, J=9.2
Hz), 7.25 (1H, d, J=8.5 Hz), 7.53 (1H, m), 7.75 (1H, d, J=9.2 Hz),
7.86 (2H, s), 8.13 (1H, s), 8.64 (1H, s). [M+H] Calc'd for
C.sub.25H.sub.23ClFN.sub.7O, 492; Found, 492.
Example 116:
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-[(3S)-3-(methylamino)piperidine-1--
carbonyl]imidazol-2-yl]-2-fluorobenzonitrile
##STR00479##
The title compound was prepared as the formic acid salt in 6%
overall yield according to the general procedure for the
preparation of Example 57. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
1.54 (1H, m), 1.64 (1H, m), 1.82 (1H, m), 2.07 (1H, m), 2.62 (3H,
s), 3.14 (1H, m), 3.32 (3H, s), 4.19 (3H, s), 7.19 (1H, d, J=8.9
Hz), 7.25 (1H, d, J=7.8 Hz), 7.53 (1H, m), 7.75 (1H, d, J=9.2 Hz),
7.86 (2H, s), 8.12 (1H, s). [M+H] Calc'd for
C.sub.25H.sub.23ClFN.sub.7O, 492; Found, 492.
Example 117:
1-(3-Chloro-2-methylindazol-5-yl)-2-(4-cyano-3-fluorophenyl)-5-methyl-N-[-
(3R)-piperidin-3-yl]imidazole-4-carboxamide
##STR00480##
The title compound was prepared as the formic acid salt in 2%
overall yield treating Boc protected Example 97 with 1 equiv. of
NCS followed by deprotection. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
1.65 (2H, m), 1.78 (2H, m), 2.33 (3H, s), 2.65 (1H, m), 2.78 (1H,
t, J=10.3 Hz), 3.00 (1H, m), 3.10 (1H, d, J=10.4 Hz), 4.09 (1H, m),
4.19 (3H, s), 4.21 (1H, s), 7.17 (1H, d, J=8.3 Hz), 7.27 (1H, d,
J=8.7 Hz), 7.59 (1H, d, J=9.2 Hz), 7.76-7.85 (3H, m), 8.12 (1H, d,
J=8.1 Hz), 8.29 (1H, m). [M+H] Calc'd for
C.sub.25H.sub.23ClFN.sub.7O, 492; Found, 492.
Example 118:
4-[1-(3-Chloro-2-methylindazol-5-yl)-5-methyl-4-[(3S)-3-(methylamino)pipe-
ridine-1-carbonyl]imidazol-2-yl]-2-fluorobenzonitrile
##STR00481##
The title compound was prepared as the formic acid salt in 2.5%
overall yield treating Boc protected Example 98 with 1 equiv. of
NCS followed by deprotection. .sup.1H NMR (400 MHz, DMSO-d.sub.6):
1.14 (1H, s), 1.40 (2H, m), 1.76 (1H, m), 1.98 (1H, m), 2.19 (3H,
s), 2.35 (3H, d, J=25.9 Hz), 3.00 (2H, m), 4.15 (3H, s), 4.43 (1H,
m), 4.66 (1H, m), 7.19 (1H, d, J=7.5 Hz), 7.28 (1H, d, J=9.2 Hz),
7.42 (1H, m), 7.79 (1H, d, J=7.9 Hz), 7.84 (1H, s), 7.86 (1H, s),
8.23 (1H, s). [M+H] Calc'd for C.sub.26H.sub.25ClFN.sub.7O, 506;
Found, 506.
II. Biological Evaluation
Example 1: In Vitro Enzyme Inhibition Assay--LSD-1
This assay determines the ability of a test compound to inhibit
LSD1 demethylase activity. E. coli expressed full-length human LSD1
(Accession number 060341) was purchased from Active Motif (Cat
#31334).
The enzymatic assay of LSD1 activity is based on Time
Resolved-Fluorescence Resonance Energy Transfer (TR-FRET)
detection. The inhibitory properties of compounds to LSD1 were
determined in 384-well plate format under the following reaction
conditions: 0.1-0.5 nM LSD1, 50 nM H3K4me1-biotin labeled peptide
(Anaspec cat #64355), 2 .mu.M FAD in assay buffer of 50 mM HEPES,
pH7.3, 10 mM NaCl, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/ml BSA.
Reaction product was determined quantitatively by TR-FRET after the
addition of detection reagent Phycolink
Streptavidin-allophycocyanin (Prozyme) and Europium-anti-unmodified
histone H3 lysine 4 (H3K4) antibody (PerkinElmer) in the presence
of LSD1 inhibitor such as 1.8 mM of Tranylcypromine hydrochloride
(2-PCPA) in LANCE detection buffer (PerkinElmer) to final
concentration of 12.5 nM and 0.25 nM respectively.
The assay reaction was performed according to the following
procedure: 2 .mu.L of the mixture of 150 nM H3K4me1-biotin labeled
peptide with 2 .mu.L of 11-point serial diluted test compound in 3%
DMSO were added to each well of plate, followed by the addition of
2 .mu.L of 0.3 nM LSD1 and 6 .mu.M of FAD to initiate the reaction.
The reaction mixture was then incubated at room temperature for one
hour, and terminated by the addition of 6 .mu.L of 1.8 mM 2-PCPA in
LANCE detection buffer containing 25 nM Phycolink
Streptavidin-allophycocyanin and 0.5 nM Europium-anti-unmodified
H3K4 antibody. Enzymatic reaction is terminated within 15 minutes
if 0.5 LSD1 enzyme is used in the plate. Plates were read by
EnVision Multilabel Reader in TR-FRET mode (excitation at 320 nm,
emission at 615 nm and 665 nm) after 1 hour incubation at room
temperature. A ratio was calculated (665/615) for each well and
fitted to determine inhibition constant (IC.sub.50).
The ability of the compounds disclosed herein to inhibit LSD1
activity was quantified and the respective IC.sub.50 value was
determined. Table 3 provides the IC.sub.50 values of various
substituted heterocyclic compounds disclosed herein.
TABLE-US-00003 TABLE 3 Chemical LSD1 Synthesis IC.sub.50 Example
Name (.mu.M) 1
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-methyl-2-p-tolyl- A
1H-pyrrol-3-yl]-benzonitrile 2
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-2-(4-methoxy- A
phenyl)-1-methyl-1H-pyrrol-3-yl]-2-fluoro-benzonitrile 3
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-(2-hydroxy-ethyl)- A
2-p-tolyl-1H-pyrrol-3-yl]-benzonitrile 4
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-(2-hydroxy-ethyl)- A
2-p-tolyl-1H-pyrrol-3-yl]-2-fluoro-benzonitrile 5
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-methyl-2-(6- A
methyl-pyridin-3-yl)-1H-pyrrol-3-yl]-benzonitrile 6
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-methyl-2-pyridin- A
4-yl-1H-pyrrol-3-yl]-benzonitrile 7
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-(2-hydroxy-ethyl)- A
2-(4-methoxy-phenyl)-1H-pyrrol-3-yl]-benzonitrile 8
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-(2-hydroxy-ethyl)- A
2-(4-methoxy-phenyl)-1H-pyrrol-3-yl]-2-fluoro-benzonitrile 9
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-(3-hydroxy- A
propyl)-2-(4-methoxy-phenyl)-1H-pyrrol-3-yl]-2-fluoro- benzonitrile
10 4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-methyl-2-(1- A
methyl-1H-benzoimidazol-5-yl)-1H-pyrrol-3-yl]-2-fluoro-
benzonitrile 11
4-[4-[(3R)-3-aminopiperidine-1-carbonyl]-5-methyl-1-(4- A
methylphenyl)imidazol-2-yl]benzonitrile 12
4-[4-[(3R)-3-aminopiperdine-1-carbonyl]-1-(4- A
methoxyphenyl)-5-methylimidazol-2-yl]-2-fluorobenzonitrile 13
4-[4-[(3R)-3-aminopyrrolidine-1-carbonyl]-1-(4- A
methoxyphenyl)-5-methylimidazol-2-yl]-2-fluorobenzonitrile 14
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-1-(4- A
methoxyphenyl)-5-methylimidazol-2-yl]-2-fluorobenzonitrile 15
4-[4-[(3R)-3-aminopiperidine-1-carbonyl]-1-(6- A
methoxypyridin-3-yl)-5-methylimidazol-2-yl]-2- fluorobenzonitrile
16 4-[4-[(3R)-3-aminopiperidine-1-carbonyl]-1-(3-fluoro-4- A
methoxyphenyl)-5-methylimidazol-2-yl]-2-fluorobenzonitrile 17
4-[4-[(3S)-3-aminopiperidine-1-carbonyl]-1-(3-fluoro-4- A
methoxyphenyl)-5-methylimidazol-2-yl]-2-fluorobenzonitrile 18
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-1-(3-fluoro-4- A
methoxyphenyl)-5-methylimidazol-2-yl]-2-fluorobenzonitrile 19
4-[4-[(3R)-3-aminopiperidine-1-carbonyl]-1-(3-fluoro-4- A
methoxyphenyl)imidazol-2-yl]-2-fluorobenzonitrile 20
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-1-(3-fluoro-4- A
methoxyphenyl)imidazol-2-yl]-2-fluorobenzonitrile 21
4-[4-[(3R)-3-aminopiperidine-1-carbonyl]-5-methyl-1-(2- A
methylindazol-5-yl)imidazol-2-yl]-2-fluorobenzonitrile 22
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-5-methyl-1-(2- A
methylindazol-5-yl)imidazol-2-yl]-2-fluorobenzonitrile 23
4-[4-[(3R)-3-aminopiperidine-1-carbonyl]-5-methyl-1-(1- A
methylindazol-5-yl)imidazol-2-yl]-2-fluorobenzonitrile 24
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-5-methyl-1-(1- A
methylindazol-5-yl)imidazol-2-yl]-2-fluorobenzonitrile 25
4-[4-[(3R)-3-aminopiperidine-1-carbonyl]-1-(2-methylindazol- A
5-yl)imidazol-2-yl]-2-fluorobenzonitrile 26
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-1-(2- A
methylindazol-5-yl)imidazol-2-yl]-2-fluorobenzonitrile 27
4-[4-[(3R)-3-aminopiperidine-1-carbonyl]-1-(1-methylindazol- A
5-yl)imidazol-2-yl]-2-fluorobenzonitrile 28
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-1-(1- A
methylindazol-5-yl)imidazol-2-yl]-2-fluorobenzonitrile 29
4-{5-[((3R)-3-aminopiperidyl)carbonyl]-1-methyl-2-(2- A
methyl(2H-indazol-5-yl))pyrrol-3-yl}-2- fluorobenzenecarbonitrile
30 N-((3R)pyrrolidin-3-yl)[4-(4-cyano-3-fluorophenyl)-1-methyl- A
5-(2-methyl(2H-indazol-5-yl))pyrrol-2-yl]carboxamide 31
N-(2-aminoethyl)[4-(4-cyano-3-fluorophenyl)-1-methyl-5-(2- A
methyl(2H-indazol-5-yl))pyrrol-2-yl]-N-methylcarboxamide 32
[4-(4-cyano-3-fluorophenyl)-1-methyl-5-(2-methyl(2H- A
indazol-5-yl))pyrrol-2-yl]-N-[2- (methylamino)ethyl]carboxamide 33
N-[((3S)pyrrolidin-3-yl)methyl][4-(4-cyano-3-fluorophenyl)-1- A
methyl-5-(2-methyl(2H-indazol-5-yl))pyrrol-2-yl]carboxamide 34
(R)-4-(5-(3-aminopiperidine-1-carbonyl)-1-(3-hydroxypropyl)- A
2-(2-methyl-2H-indazol-5-yl)-1H-pyrrol-3-yl)-2- fluorobenzonitrile
35 (R)-4-(5-(3-aminopiperidine-1-carbonyl)-1-(2-hydroxyethyl)- A
2-(2-methyl-2H-indazol-5-yl)-1H-pyrrol-3-yl)-2- fluorobenzonitrile
36 (R)-4-(5-(3-aminopiperidine-1-carbonyl)-1-(2-methoxyethyl)- A
2-(2-methyl-2H-indazol-5-yl)-1H-pyrrol-3-yl)-2- fluorobenzonitrile
37 (R)-2-(5-(3-aminopiperidine-1-carbonyl)-3-(4-cyano-3- A
fluorophenyl)-2-(4-methoxyphenyl)-1H-pyrrol-1-yl)acetamide 38
4-(5-((R)-3-aminopiperidine-1-carbonyl)-1-((R)-2,3- A
dihydroxypropyl)-2-(2-methyl-2H-indazol-5-yl)-1H-pyrrol-3-
yl)-2-fluorobenzonitrile 39
4-(5-((R)-3-aminopiperidine-1-carbonyl)-1-((S)-2,3- A
dihydroxypropyl)-2-(2-methyl-2H-indazol-5-yl)-1H-pyrrol-3-
yl)-2-fluorobenzonitrile 40
N-[((3R)pyrrolidin-3-yl)methyl][4-(4-cyano-3-fluorophenyl)-1- A
methyl-5-(2-methyl(2H-indazol-5-yl))pyrrol-2-yl]carboxamide 41
4-{5-[((3R)-3-aminopiperidyl)carbonyl]-3-(4-cyano-3- A
fluorophenyl)-2-(4-methoxyphenyl)pyrrolyl}butanoic acid 42
4-{5-[((3R)-3-aminopiperidyl)carbonyl]-3-(4-cyano-3- A
fluorophenyl)-2-(4-methoxyphenyl)pyrrolyl}butanamide 43
4-[4-(4-Aminopiperidine-1-carbonyl)-5-methyl-1-(2- A
methylindazol-5-yl)imidazol-2-yl]-2-fluorobenzonitrile 44
N-(2-Aminoethyl)-2-(4-cyano-3-fluorophenyl)-N,5-dimethyl- A
1-(2-methylindazol-5-yl)imidazole-4-carboxamide 45
2-(4-Cyano-3-fluorophenyl)-5-methyl-1-(2-methylindazol-5- A
yl)-N-piperidin-3-ylimidazole-4-carboxamide 46
2-(4-Cyano-3-fluorophenyl)-5-methyl-1-(2-methylindazol-5- A
yl)-N-pyrrolidin-3-ylimidazole-4-carboxamide 47
4-[4-[(3R)-3-Aminopiperdine-1-carbonyl]-1-(6-fluro-2- A
methylindazol-5-yl)-5-methylimidazol-2-yl]-2- fluorobenzonitrile 48
4-[4-[(3S)-3-(Dimethylamino)pyrrolidine-1-carbonyl]-1-(6- A
fluoro-2-methylindazol-5-yl)-5-methylimidazol-2-yl]-2-
fluorobenzonitrile 49
2-Fluoro-4-[1-(6-fluoro-2-methylindazol-5-yl)-5-methyl-4- A
[(3S)-3-(methylamino)pyrrolidine-1-carbonyl]imidazol-2-
yl]benzonitrile 50
4-[4-[(3S)-3-Aminopyrrolidine-1-carbonyl]-1-(7-fluro-2- A
methylindazol-5-yl)-5-methylimidazol-2-yl]-2- fluorobenzonitrile 51
2-Fluoro-4-[1-(7-fluoro-2-methylindazol-5-yl)-5-methyl-4- A
[(3S)-3-(methylamino)pyrrolidine-1-carbonyl]imidazol-2-
yl]benzonitrile 52
4-[4-[(3S)-3-(Dimethylamino_pyrrolidine-1-carbonyl]-1-(7- A
fluoro-2-methylindazol-5-yl)-5-methylimidazol-2-yl]-2-
fluorobenzonitrile 53
4-[4-[(3R)-3-Aminopiperdine-1-carbonyl]-1-(3-chloro-2- A
methylindazol-5-yl)-5-methylimidazol-2-yl]-2- fluorobenzonitrile 54
4-[1-(3-Chloro-2-methylindazol-5-yl)-5-methyl-4-[(3S)-3- A
(methylamino)pyrrolidine-1-carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 55
4-[1-(3-Chloro-2-methylindazol-5-yl)-5-methyl-4-[(3R)-3- A
(methylamino)piperidine-1-carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 56
1-(3-Chloro-2-methylindazol-5-yl)-2-(4-cyano-3- A
fluorophenyl)-5-methyl-N-[(3R)-1-methylpiperidin-3-
yl]imidazole-4-carboxamide 57
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-[(3S)-3- A
(dimethylamino)pyrrolidine-1-carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 58
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-[(3S)-3- A
(dimethylamino)pyrrolidine-1-carbonyl]-5-fluoroimidazol-2-
yl]-2-fluorobenzonitrile 59
1-(3-Chloro-2-methylindazol-5-yl)-2-(4-cyano-3- A
fluorophenyl)-N-[(3R)-1-methylpiperidin-3-yl]imidazole-4-
carboxamide 60
2-(4-Cyano-3-fluorophenyl)-5-methyl-1-(2-methylindazol-5- A
yl)-N-[(3R)-1-methylpiperidin-3-yl]imidazole-4-carboxamide 61
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-1-(3-chloro-2- A
methylindazol-5-yl)-5-fluoroimidazol-2-yl]-2- fluorobenzonitrile 62
2-(4-Cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)-5- A
methyl-N-[(3R)-piperidin-3-yl]imidazole-4-carboxamide 63
2-(4-Cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)-5- A
methyl-N-[(3S)-piperidin-3-yl]imidazole-4-carboxamide 64
2-Fluoro-4-[1-(3-fluoro-4-methoxyphenyl)-5-methyl-4-[(3S)-3- A
(methylamino)pyrrolidine-1-carbonyl]imidazol-2- yl]benzonitrile 65
2-Fluoro-4-[1-(3-fluoro-4-methoxyphenyl)-4-[(3S)-3- A
(methylamino)pyrrolidine-1-carbonyl]imidazol-2- yl]benzonitrile 66
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5-chloro-1-(3- A
fluoro-4-methoxyphenyl)imidazol-2-yl]-2-fluorobenzonitrile 67
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5-fluoro-1-(3- A
fluoro-4-methoxyphenyl)imidazol-2-yl]-2-fluorobenzonitrile 68
2-Fluoro-4-[5-fluoro-1-(3-fluoro-4-methoxyphenyl)-4-[(3S)-3- A
(methylamino)pyrrolidine-1-carbonyl]imidazol-2- yl]benzonitrile 69
2-Fluoro-4-[1-(4-methoxyphenyl)-5-methyl-4-[(3S)-3- A
(methylamino)pyrrolidine-1-carbonyl]imidazol-2- yl]benzonitrile 70
2-Fluoro-4-[1-(4-methoxyphenyl)-5-methyl-4-[(3R)-3- A
(methylamino)piperidine-1-carbonyl]imidazol-2- yl]benzonitrile 71
2-Fluoro-4-[1-(4-methoxyphenyl)-4-[(3S)-3- A
(methylamino)pyrrolidine-1-carbonyl]imidazol-2- yl]benzonitrile 72
2-Fluoro-4-[1-(4-methoxyphenyl)-4-[(3R)-3- A
(methylamino)piperidine-1-carbonyl]imidazol-2- yl]benzonitrile 73
2-Fluoro-4-[5-fluoro-1-(4-methoxyphenyl)-4-[(3S)-3- A
(methylamino)pyrrolidine-1-carbonyl[imidazol-2- yl]benzonitrile 74
2-Fluoro-4-[5-fluoro-1-(4-methoxyphenyl)-4-[(3R)-3- A
(methylamino)piperidine-1-carbonyl]imidazol-2- yl]benzonitrile 75
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5-chloro-1-(2- A
methylindazol-5-yl)imidazol-2-yl]-2-fluorobenzonitrile 76
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5-chloro-1-(3- A
chloro-2-methylindazol-5-yl)imidazol-2-yl]-2- fluorobenzonitrile 77
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5-fluoro-1-(2- A
methylindazol-5-yl)imidazol-2-yl]-2-fluorobenzonitrile 78
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-1-(6- A
cyclopropylpyridin-3-yl)-5-methylimidazol-2-yl]-2-
fluorobenzonitrile 79
4-[4-[(3S)-3-Aminopyrrolidine-1-carbonyl]-1-(6- A
cyclopropylpyridin-3-yl)-5-methylimidazol-2-yl]-2-
fluorobenzonitrile 80
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5-chloro-1-(6- A
cyclopropylpyridin-3-yl)imidazol-2-yl]-2-fluorobenzonitrile 81
4-[4-[(3S)-3-Aminopyrrolidine-1-carbonyl]-5-chloro-1-(6- A
cyclopropylpyridin-3-yl)imidazol-2-yl]-2-fluorobenzonitrile 82
2-(4-Cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)-5- A
methyl-N-[(3R)-pyrrolidin-3-yl]imidazole-4-carboxamide 83
2-(4-Cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)-5- A
methyl-N-[(3S)-pyrrolidin-3-yl]imidazole-4-carboxamide 84
5-Chloro-2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4- A
methoxyphenyl)-N-[(3R)-piperidin-3-yl]imidazole-4- carboxamide 85
5-Chloro-2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4- A
methoxyphenyl)-N-[(3S)-piperidin-3-yl]imidazole-4- carboxamide 86
2-(4-Cyano-3-fluorophenyl)-5-fluoro-1-(3-fluoro-4- A
methoxyphenyl)-N-[(3R)-piperidin-3-yl]imidazole-4- carboxamide 87
2-(4-Cyano-3-fluorophenyl)-1-(3-fluoro-4-methoxyphenyl)-5- A
methyl-N-piperidin-4-ylimidazole-4-carboxamide 88
4-[4-[3-(Aminomethyl)azetidine-1-carbonyl]-1-(3-fluoro-4- A
methoxyphenyl)-5-methylimidazol-2-yl]-2-fluorobenzonitrile 89
4-[4-[(3S)-3-Aminopyrrolidine-1-carbonyl]-5-fluoro-1-(3- A
fluoro-4-methoxyphenyl)imidazol-2-yl]-2-fluorobenzonitrile 90
4-[4-(1,7-Diazaspiro[4.4]nonane-7-carbonyl)-5-methyl-1-(2- A
methylindazol-5-yl)imidazol-2-yl]-2-fluorobenzonitrile 91
4-[4-(2,6-Diazaspiro[3.4]octane-6-carbonyl)-5-methyl-1-(2- A
methylindazol-5-yl)imidazol-2-yl]-2-fluorobenzonitrile 92
4-[4-(1,7-Diazaspiro[3.4]octane-7-carbonyl)-5-methyl-1-(1- A
methylindazol-5-yl)imidazol-2-yl]-2-fluorobenzonitrile 93
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-(1,7- A
diazaspiro[3.4]octane-7-carbonyl)imidazol-2-yl]-2-
fluorobenzonitrile 94
4-[4-[(3S)-3-(Dimethylamino)pyrrolidine-1-carbonyl]-5- A
methyl-1-(2-methylindazol-5-yl)imidazol-2-yl]-2- fluorobenzonitrile
95 4-[4-[(3S)-3-(Dimethylamino)pyrrolidine-1-carbonyl]-5- A
methyl-1-(1-methylindazol-5-yl)imidazol-2-yl]-2- fluorobenzonitrile
96 4-[1-(3-Chloro-2-methylindazol-5-yl)-4-[(3S)-3- A
(dimethylamino)pyrrolidine-1-carbonyl]-5-methylimidazol-2-
yl]-2-fluorobenzonitrile 97
2-Fluoro-4-[5-methyl-4-[(3S)-3-(methylamino)piperidine-1- A
carbonyl]-1-(2-methylindazol-5-yl)imidazol-2-yl]benzonitrile 98
2-Fluoro-4-[5-methyl-4-[(3R)-3-(methylamino)piperidine-1- A
carbonyl]-1-(2-methylindazol-5-yl)imidazol-2-yl]benzonitrile 99
4-[4-[(3S)-3-(Dimethylamino)pyrrolidine-1-carbonyl]-1-(2- A
methylindazol-5-yl)imidazol-2-yl]-2-fluorobenzonitrile 100
4-[5-Chloro-4-[(3S)-3-(dimethylamino)pyrrolidine-1- A
carbonyl]-1-(2-methylindazol-5-yl)imidazol-2-yl]-2-
fluorobenzonitrile 101
4-[5-Chloro-1-(3-chloro-2-methylindazol-5-yl)-4-[(3S)-3- A
(dimethylamino)pyrrolidine-1-carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 102
4-[4-[(3S)-3-(Dimethylamino)pyrrolidine-1-carbonyl]-1-(2,3- A
dimethylindazol-5-yl)-5-methylimidazol-2-yl]-2- fluorobenzonitrile
103 4-[1-(2,3-Dimethylindazol-5-yl)-5-methyl-4-[(3S)-3- A
(methylamino)pyrrolidine-1-carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 104
2-(4-Cyano-3-fluorophenyl)-1-(2,3-dimethylindazol-5-yl)-5- A
methyl-N-[(3R)-piperidin-3-yl]imidazole-4-carboxamide 105
4-[1-(2,3-Dimethylindazol-5-yl)-5-methyl-4-[(3R)-3- A
(methylamino)piperidine-1-carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 106
1-(3-Chloro-2-methylindazol-5-yl)-2-(4-cyano-3- A
fluorophenyl)-N-[(3R)-1-methylpyrrolidin-3-yl]imidazole-4-
carboxamide 107 1-(3-Chloro-2-methylindazol-5-yl)-2-(4-cyano-3- A
fluorophenyl)-N-[(3S)-1-methylpyrrolidin-3-yl]imidazole-4-
carboxamide 108
2-(4-Cyano-3-fluorophenyl)-5-methyl-1-(2-methylindazol-5- A
yl)-N-[(3R)-1-methylpyrrolidin-3-yl]imidazole-4-carboxamide 109
2-(4-Cyano-3-fluorophenyl)-5-methyl-1-(2-methylindazol-5- A
yl)-N-[(3S)-1-methylpyrrolidin-3-yl]imidazole-4-carboxamide 110
4-[1-(3-Chloro-6-fluoro-2-methylindazol-5-yl)-4-[(3S)-3- A
(dimethylamino)pyrrolidine-1-carbonyl]-5-methylimidazol-2-
yl]-2-fluorobenzonitrile 111
4-[1-(3-Chloro-6-fluoro-2-methylindazol-5-yl)-5-methyl-4- A
[(3S)-3-(methylamino)pyrrolidine-1-carbonyl]imidazol-2-yl]-
2-fluorobenzonitrile 112
4-[1-(3-Chloro-6-fluoro-2-methylindazol-5-yl)-4-[(3S)-3- A
(dimethylamino)pyrrolidine-1-carbonyl]-5-methylimidazol-2-
yl]-2-fluorobenzonitrile 113
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-[(3S)-3- A
(methylamino)pyrrolidine-1-carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 114
1-(3-Chloro-2-methylindazol-5-yl)-2-(4-cyano-3- A
fluorophenyl)-N-[(3R)-piperidin-3-yl]imidazole-4- carboxamide 115
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-[(3R)-3- A
(methylamino)piperidine-1-carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 116
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-[(3S)-3- A
(methylamino)piperidine-1-carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 117
1-(3-Chloro-2-methylindazol-5-yl)-2-(4-cyano-3- A
fluorophenyl)-5-methyl-N-[(3R)-piperidin-3-yl]imidazole-4-
carboxamide 118
4-[1-(3-Chloro-2-methylindazol-5-yl)-5-methyl-4-[(3S)-3- A
(methylamino)piperidine-1-carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile Note: Biochemical assay IC.sub.50 data are
designated within the following ranges: A: .ltoreq.0.10 .mu.M B:
>0.10 .mu.M to .ltoreq.1.0 .mu.M C: >1.0 .mu.M to .ltoreq.10
.mu.M D: >10 .mu.M
Example 2: In Vitro Enzyme Inhibition Assay--MAO Selectivity
Human recombinant monoamine oxidase proteins MAO-A and MAO-B are
obtained. MAOs catalyze the oxidative deamination of primary,
secondary and tertiary amines. In order to monitor MAO enzymatic
activities and/or their inhibition rate by inhibitor(s) of
interest, a fluorescent-based (inhibitor)-screening assay is
performed. 3-(2-Aminophenyl)-3-oxopropanamine (kynuramine
dihydrobromide, Sigma Aldrich), a non-fluorescent compound is
chosen as a substrate. Kynuramine is a non-specific substrate for
both MAOs activities. While undergoing oxidative deamination by MAO
activities, kynuramine is converted into 4-hydroxyquinoline (4-HQ),
a resulting fluorescent product.
The monoamine oxidase activity is estimated by measuring the
conversion of kynuramine into 4-hydroxyquinoline. Assays are
conducted in 96-well black plates with clear bottom (Corning) in a
final volume of 100 .mu.l. The assay buffer is 100 mM HEPES, pH
7.5. Each experiment is performed in triplicate within the same
experiment.
Briefly, a fixed amount of MAO (0.25 .mu.g for MAO-A and 0.5 .mu.g
for AO-B) is incubated on ice for 15 minutes in the reaction
buffer, in the absence and/or in the presence of various
concentrations of compounds as disclosed herein (e.g., from 0 to 50
.mu.M, depending on the inhibitor strength). Tranylcypromine
(Biomol International) is used as a control for inhibition.
After leaving the enzyme(s) interacting with the test compound, 60
to 90 .mu.M of kynuramine is added to each reaction for MAO-B and
MAO-A assay respectively, and the reaction is left for 1 hour at
37.degree. C. in the dark. The oxidative deamination of the
substrate is stopped by adding 50 .mu.l of 2N NaOH. The conversion
of kynuramine to 4-hydroxyquinoline, is monitored by fluorescence
(excitation at 320 nm, emission at 360 nm) using a microplate
reader (Infinite 200, Tecan). Arbitrary units are used to measure
levels of fluorescence produced in the absence and/or in the
presence of test compound.
The maximum of oxidative deamination activity is obtained by
measuring the amount of 4-hydroxyquinoline formed from kynuramine
deamination in the absence of test compound and corrected for
background fluorescence. The Ki (IC.sub.50) of each inhibitor is
determined at Vmax/2.
Example 3: LSD1 CD11b Cellular Assay
To analyze LSD1 inhibitor efficacy in cells, a CD11b flow cytometry
assay was performed. LSD1 inhibition induces CD11b expression in
THP-1 (AML) cells which can be measured by flow cytometry. THP-1
cells were seeded at 100,000 cells/well in 10% Fetal Bovine Serum
containing RPMI 1640 media in a 24 well plate with a final volume
of 500 .mu.L per well. LSD1 test compounds were serially diluted in
DMSO. The dilutions were added to each well accordingly to a final
concentration of 0.2% DMSO. The cells were incubated at 37 degrees
Celsius in 5% CO.sub.2 for 4 days. 250 .mu.L of each well was
transferred to a well in a 96 well round bottom plate. The plate
was centrifuged at 1200 rpm at 4 degrees Celsius in a Beckman
Coulter Alegra 6KR centrifuge for 5 minutes. The media was removed
leaving the cells at the bottom of the wells. The cells were washed
in 100 .mu.L cold HBSS (Hank's Balanced Salt Solution) plus 2% BSA
(Bovine Serum Albumin) solution and centrifuged at 1200 rpm at 4
degrees Celsius for 5 minutes. The wash was removed. The cells were
resuspended in 100 .mu.L HBSS plus 2% BSA containing 1:15 dilution
of APC conjugated mouse anti-CD11b antibody (BD Pharmingen Cat
#555751) and incubated on ice for 25 minutes. The cells were
centrifuged and washed two times in 100 .mu.l HBSS plus 2% BSA.
After the final spin the cells were resuspended in 100 .mu.L HBSS
plus 2% BSA containing 1 ug/mL DAPI
(4',6-diamidino-2-phenylindole). The cells were then analyzed by
flow cytometry in a BD FACSAria machine. Cells were analyzed for
CD11b expression. The percent of CD11b expressing cells for each
inhibitor concentration was used to determine an IC.sub.50 curve
for each compound analyzed.
Table 4 provides the cellular IC.sub.50 values of various
substituted heterocyclic compounds disclosed herein.
TABLE-US-00004 TABLE 4 Cellu- Chemical lar Synthesis IC.sub.50
Example Name (.mu.M) 1
4-[5-(R)-amino-piperidine-1-carbonyl)-1-methyl-2- A
p-tolyl-1H-pyrrol-3-yl]-benzonitrile 2
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-2-(4- A
methoxy-phenyl)-1-methyl-1H-pyrrol-3-yl]-2-fluoro- benzonitrile 3
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-(2- A
hydroxy-ethyl)-2-p-tolyl-1H-pyrrol-3-yl]-benzonitrile 4
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-(2- A
hydroxy-ethyl)-2-p-tolyl-1H-pyrrol-3-yl]-2-fluoro- benzonitrile 5
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-methyl-2- A
(6-methyl-pyridin-3-yl)-1H-pyrrol-3-yl]-benzonitrile 6
4-[5-(R)-amino-piperidine-1-carbonyl)-1-methyl-2- A
pyridin-4-yl-1H-pyrrol-3-yl]-benzonitrile 7
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-(2- A
hydroxy-ethyl)-2-(4-methoxy-phenyl)-1H-pyrrol-3-yl] benzonitrile 8
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-(2- A
hydroxy-ethyl)-2-(4-methoxy-phenyl)-1H-pyrrol-3-yl]
2-fluoro-benzonitrile 9
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-(3- A
hydroxy-propyl)-2-(4-methoxy-phenyl)-1H-pyrrol-3-
yl]-2-fluoro-benzonitrile 10
4-[5-(3-(R)-amino-piperidine-1-carbonyl)-1-methyl-2- A
(1-methyl-1H-benzoimidazol-5-yl)-1H-pyrrol-3-yl]-2-
fluoro-benzonitrile 11
4-[4-[(3R)-3-aminopiperidine-1-carbonyl]-5-methyl-1- A
(4-methylphenyl)imidazol-2-yl]benzonitrile 12
4-[4-[(3R)-3-aminopiperidine-1-carbonyl]-5-methyl-1 A
methoxyphenyl)-5-methylimidazol-2-yl]-2- fluorobenzonitrile 13
4-[4-[(3R)-3-aminopyrrolidine-1-caronlyl]-1-(4- B
methoxyphenyl)-5-methylimidazol-2-yl]-2- fluorobenzonitrile 14
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-1-(6- A
methoxyphenyl)-5-methylimidazol-2-yl]-2- fluorobenzonitrile 15
4-[4-[(3R)-3-aminopiperdine-1-carbonyl]-1-(6- B
methoxypyridin-3-yl)-5-methylimidazol-2-yl]-2- fluorobenzonitrile
16 4-[4-[(3R)-3-aminopiperdine-1-carbonlyl]-1-(3-fluoro- A
4-methoxyphenyl)-5-methylimidazol-2-yl]-2- fluorobenzonitrile 17
4-[4-[(3S)-3-aminopiperdine-1-carbonyl]-1-(3-fluoro- B
4-methoxyphenyl)-5-methylimidazol-2-yl]-2- fluorobenzonitrile 18
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-1-(3-fluoro- A
4-methoxyphenyl)-5-methylimidazol-2-yl]-2- fluorobenzonitrile 19
4-[4-[(3R)-3-aminopiperdine-1-carbonyl]-1-(3-fluoro- A
4-methoxyphenyl)imidazol-2-yl]-2-fluorobenzonitrile 20
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-1-(3-fluoro- A
4-methoxyphenyl)imidazol-2-yl]-2-fluorobenzonitrile 21
4-[4-[(3R)-3-aminopiperdine-1-carbonyl]-5-methyl-1 A
(2-methylindazol-5-yl)imidazol-2-yl]-2- fluorobenzonitrile 22
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-5-methyl-1- A
(2-methylindazol-5-yl)imidazol-2-yl]-2- fluorobenzonitrile 23
4-[4-[(3R)-3-aminopiperdine-1-carbonyl]-5-methyl-1- A
(1-methylindazol-5-yl)imidazol-2-yl]-2- fluorobenzonitrile 24
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-5-methyl-1- A
(1-methylindazol-5-yl)imidazol-2-yl]-2- fluorobenzonitrile 29
4-{5-[((3R)-3-aminopiperidyl)carbonyl]-1-methyl-2-(2- A
methyl(2H-indazol-5-yl))pyrrol-3-yl}-2- fluorobenzenecarbonitrile
30 N-((3R)pyrrolidin-3-yl)[4-(4-cyano-3-fluorophenyl)-1- A
methyl-5-(2-methyl(2H-indazol-5-yl))pyrrol-2- yl]carboxamide 31
N-(2-aminoethyl)[4-(4-cyano-3-fluorophenyl)-1- A
methyl-5-(2-methyl(2H-indazol-5-yl))pyrrol-2-yl]-N-
methylcarboxamide 32
[4-(4-cyano-3-fluorophenyl)-1-methyl-5-(2-methyl(2H- A
indazol-5-yl))pyrrol-2-yl]-N-[2- (methylamino)ethyl]carboxamide 33
N-[((3S)pyrrolidin-3-yl)methyl][4-(4-cyano-3- A
fluorophenyl)-1-methyl-5-(2-methyl(2H-indazol-5-
yl))pyrrol-2-yl]carboxamide 34
(R)-4-(5-(3-aminopiperidine-1-carbonyl)-1-(3- A
hydroxypropyl)-2-(2-methyl-2H-indazol-5-yl)-1H-
pyrrol-3-yl)-2-fluorobenzonitrile 35
(R)-4-(5-(3-aminopiperidine-1-carbonyl)-1-(2- A
hydroxyethyl)-2-(2-methyl-2H-indazol-5-yl)-1H-
pyrrol-3-yl)-2-fluorobenzonitrile 36
(R)-4-(5-(3-aminopiperidine-1-carbonyl)-1-(2- A
methoxyethyl)-2-(2-methyl-2H-indazol-5-yl)-1H-
pyrrol-3-yl)-2-fluorobenzonitrile 38
4-(5-((R)-3-aminopiperidine-1-carbonyl)-1-((R)-2,3- A
dihydroxypropyl)-2-(2-methyl-2H-indazol-5-yl)-1H-
pyrrol-3-yl)-2-fluorobenzonitrile 39
4-(5-((R)-3-aminopiperidine-1-carbonyl)-1-((3S)-2,3- A
dihydroxypropyl)-2-(2-methyl-2H-indazol-5-yl)-1H-
pyrrol-3-yl)-2-fluorobenzonitrile 40
N-[((3R)pyrrolidin-3-yl)methyl][4-(4-cyano-3- A
fluorophenyl)-1-methyl-5-(2-methyl(2H-indazol-5-
yl))pyrrol-2-yl]carboxamide 41
4-{5-[((3R)-3-aminopiperidyl)carbonyl]-3-(4-cyano-3- B
fluorophenyl)-2-(4-methoxyphenyl)pyrrolyl}butanoic acid 42
4-{5-[((3R)-3-aminopiperidyl)carbonyl]-3-(4-cyano-3- A
fluorophenyl)-2-(4- methoxyphenyl)pyrrolyl}butanamide 43
4-[4-(4-Aminopiperidine-1-carbonyl)-5-methyl-1-(2- B
methylindazol-5-yl)imidazol-2-yl]-2-fluorobenzonitrile 44
N-(2-Aminoethyl)-2-(4-cyano-3-fluorophenyl)-N,5-
dimethyl-1-(2-methylindazol-5-yl)imidazole-4- carboxamide 45
2-(4-Cyano-3-fluorophenyl)-5-methyl-1-(2- A
methylindazol-5-yl)-N-piperidin-3-ylimidazole-4- carboxamide 46
2-(4-Cyano-3-fluorophenyl)-5-methyl-1-(2- A
methylindazol-5-yl)-N-pyrrolidin-3-ylimidazole-4- carboxamide 47
4-[4-[(3S)-3-(Dimethylamino)pyrrolidine-1-carbonyl]- A
2-methylindazol-5-yl)-5-methylimidazol-2-yl]-2- fluorobenzonitrile
48 4-[4-[(3S)-3-(Dimethylamino)pyrrolidine-1-carbonyl]- A
1-(6-fluoro-2-methylindazol-5-yl)-5-methylimidazol-2-
yl]-2-fluorobenzonitrile 49
2-Fluoro-4-[1-(6-fluoro-2-methylindazol-5-yl)-5- A
methyl-4-[(3S)-3-(methylamino)pyrrolidine-1-
carbonyl]imidazol-2-yl]benzonitrile 50
4-[4-[(3S)-3-Aminopyrrolidine-1-carbonyl]-1-(7- A
fluoro-2-methylindazol-5-yl)-5-methylimidazol-2-yl]-2-
fluorobenzonitrile 51
2-Fluoro-4-[1-(7-fluoro-2-methylindazol-5-yl)-5- A
methyl-4-[(3S)-3-(methylamino)pyrrolidine-1-
carbonyl]imidazol-2-yl]benzonitrile 52
4-[4-[(3S)-3-(Dimethylamino)pyrrolidine-1-carbonyl]- A
1-(7-fluoro-2-methylindazol-5-yl)-5-methylimidazol-2-
yl]-2-fluorobenzonitrile 53
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-1-(3-chloro- A
2-methylindazol-5-yl)-5-methylimidazol-2-yl]-2- fluorobenzonitrile
54 4-[1-(3-Chloro-2-methylindazol-5-yl)-5-methyl-4- A
[(3S)-3-(methylamino)pyrrolidine-1-carbonyl]imidazol-
2-yl]-2-fluorobenzonitrile 55
4-[1-(3-Chloro-2-methylindazol-5-yl)-5-methyl-4- A
[(3R)-3-(methylamino)piperidine-1-carbonyl]imidazol-
2-yl]-2-fluorobenzonitrile 56
1-(3-Chloro-2-methylindazol-5-yl)-2-(4-cyano-3- A
fluorophenyl)-5-methyl-N-[(3R)-1-methylpiperidin-3-
yl]imidazole-4-carboxamide 57
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-[(3S)-3- A
(dimethylamino)pyrrolidine-1-carbonyl]imidazol-2-yl]-
2-fluorobenzonitrile 58
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-[(3S)-3- A
(dimethylamino)pyrrolidine-1-carbonyl]-5-
fluoroimidazol-2-yl]-2-fluorobenzonitrile 59
1-(3-Chloro-2-methylindazol-5-yl)-2-(4-cyano-3- A
fluorophenyl)-N-[(3R)-1-methylpiperidin-3-
yl]imidazole-4-carboxamide 60
2-(4-Cyano-3-fluorophenyl)-5-methyl-1-(2- A
methylindazol-5-yl)-N-[(3R)-1-methylpiperidin-3-
yl]imidazole-4-carboxamide 61
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-1-(3-chloro- A
2-methylindazol-5-yl)-5-fluoroimidazol-2-yl]-2- fluorobenzonitrile
62 2-(4-Cyano-3-fluorophenyl)-1-(3-fluoro-4- A
methoxyphenyl)-5-methyl-N-[(3R)-piperidin-3-
yl]imidazole-4-carboxamide 63
2-(4-Cyano-3-fluorophenyl)-1-(3-fluoro-4- A
methoxyphenyl)-5-methyl-N-[(3S)-piperidin-3-
yl]imidazole-4-carboxamide 64
2-Fluoro-4-[1-(3-fluoro-4-methoxyphenyl)-5-methyl-4- A
[(3S)-3-(methylamino)pyrrolidine-1-carbonyl]imidazol-
2-yl]benzonitrile 65
2-Fluoro-4-[1-(3-fluoro-4-methoxyphenyl)-4-[(3S)-3- A
(methylamino)pyrrolidine-1-carbonyl]imidazol-2- yl]benzonitrile 66
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5-chloro-1- A
(3-fluoro-4-methoxyphenyl)imidazol-2-yl]-2- fluorobenzonitrile 67
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5-fluoro-1- A
(3-fluoro-4-methoxyphenyl)imidazol-2-yl]-2- fluorobenzonitrile 68
2-Fluoro-4-[5-fluoro-1-(3-fluoro-4-methoxyphenyl)-4- A
[(3S)-3-(methylamino)pyrrolidine-1-carbonyl]imidazol-
2-yl]benzonitrile 69
2-Fluoro-4-[1-(4-methoxyphenyl)-5-methyl-4-[(3S)-3- A
(methylamino)pyrrolidine-1-carbonyl]imidazol-2- yl]benzonitrile 70
2-Fluoro-4-[1-(4-methoxyphenyl)-5-methyl-4-[(3R)-3- A
(methylamino)piperidine-1-carbonyl]imidazol-2- yl]benzonitrile 71
2-Fluoro-4-[1-(4-methoxyphenyl)-4-[(3S)-3- A
(methylamino)pyrrolidine-1-carbonyl]imidazol-2- yl]benzonitrile 72
2-Fluoro-4-[1-(4-methoxyphenyl)-4-[(3R)-3- A
(methylamino)piperidine-1-carbonyl]imidazol-2- yl]benzonitrile 73
2-Fluoro-4-[5-fluoro-1-(4-methoxyphenyl)-4-[(3S)-3- A
(methylamino)pyrrolidine-1-carbonyl]imidazol-2- yl]benzonitrile 74
2-Fluoro-4-[5-fluoro-1-(4-methoxyphenyl)-4-[(3R)-3- A
(methylamino)piperidine-1-carbonyl]imidazol-2- yl]benzonitrile 75
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5-chloro-1- A
(2-methylindazol-5-yl)imidazol-2-yl]-2- fluorobenzonitrile 76
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5-chloro-1- A
(3-chloro-2-methylindazol-5-yl)imidazol-2-yl]-2- fluorobenzonitrile
77 4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5-fluoro-1- A
(2-methylindazol-5-yl)imidazol-2-yl]-2- fluorobenzonitrile 78
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-1-(6- B
cyclopropylpyridin-3-yl)-5-methylimidazol-2-yl]-2-
fluorobenzonitrile 79
4-[4-[(3S)-3-Aminopyrrolidine-1-carbonyl]-1-(6- A
cyclopropylpyridin-3-yl)-5-methylimidazol-2-yl]-2-
fluorobenzonitrile 80
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5-chloro-1- B
(6-cyclopropylpyridin-3-yl)imidazol-2-yl]-2- fluorobenzonitrile 81
4-[4-[(3S)-3-Aminopyrrolidine-1-carbonyl]-5-chloro-1- A
(6-cyclopropylpyridin-3-yl)imidazol-2-yl]-2- fluorobenzonitrile 82
2-(4-Cyano-3-fluorophenyl)-1-(3-fluoro-4- B
methoxyphenyl)-5-methyl-N-[(3R)-pyrrolidin-3-
yl]imidazole-4-carboxamide 83
2-(4-Cyano-3-fluorophenyl)-1-(3-fluoro-4- B
methoxyphenyl)-5-methyl-N-[(3S)-pyrrolidin-3-
yl]imidazole-4-carboxamide 84
5-Chloro-2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4- A
methoxyphenyl)-N-[(3R)-piperidin-3-yl]imidazole-4- carboxamide 85
5-Chloro-2-(4-cyano-3-fluorophenyl)-1-(3-fluoro-4- B
methoxyphenyl)-N-[(3S)-piperidin-3-yl]imidazole-4- carboxamide 86
2-(4-Cyano-3-fluorophenyl)-5-fluoro-1-(3-fluoro-4- B
methoxyphenyl)-N-[(3R)-piperidin-3-yl]imidazole-4- carboxamide 87
2-(4-Cyano-3-fluorophenyl)-1-(3-fluoro-4- B
methoxyphenyl)-5-methyl-N-piperidin-4-ylimidazole- 4-carboxamide 88
4-[4-[3-(Aminomethyl)azetidine-1-carbonyl]-1-(3- A
fluoro-4-methoxyphenyl)-5-methylimidazol-2-yl]-2-
fluorobenzonitrile 89
4-[4-[(3S)-3-Aminopyrrolidine-1-carbonyl]-5-fluoro-1- B
(3-fluoro-4-methoxyphenyl)imidazol-2-yl]-2- fluorobenzonitrile 90
4-[4-(1,7-Diazaspiro[4.4]nonane-7-carbonyl)-5-methyl- B
1-(2-methylindazol-5-yl)imidazol-2-yl]-2- fluorobenzonitrile 91
4-[4-(2,6-Diazaspiro[3.4]octane-6-carbonyl)-5-methyl- A
1-(2-methylindazol-5-yl)imidazol-2-yl]-2- fluorobenzonitrile 92
4-[4-(1,7-Diazaspiro[3.4]octane-7-carbonyl)-5-methyl- B
1-(1-methylindazol-5-yl)imidazol-2-yl]-2- fluorobenzonitrile 93
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-(1,7- B
diazaspiro[3.4]octane-7-carbonyl)imidazol-2-yl]-2-
fluorobenzonitrile 94
4-[4-[(3S)-3-(Dimethylamino)pyrrolidin-1-carbonyl]- A
5-methyl-1-(2-methylindazol-5-yl)imidazol-2-yl]-2-
fluorobenzonitrile 95
4-[4-[(3S)-3-(Dimethylamino)pyrrolidine-1-carbonyl]- A
5-methyl-1-(1-methylindazol-5-yl)imidazol-2-yl]-2-
fluorobenzonitrile 96
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-[(3S)-3- A
(dimethylamino)pyrrolidine-1-carbonyl]-5-
methylimidazol-2-yl]-2-fluorobenzonitrile 97
2-Fluoro-4-[5-methyl-4-[(3S)-3- A
(methylamino)piperidine-1-carbonyl]-1-(2-
methylindazol-5-yl)imidazol-2-yl]benzonitrile 98
2-Fluoro-4-[5-methyl-4-[(3R)-3- A
(methylamino)piperidine-1-carbonyl]-1-(2-
methylindazol-5-yl)imidazol-2-yl]benzonitrile 99
4-[4-[(3S)-3-(Dimethylamino)pyrrolidine-1-carbonyl]- B
1-(2-methylindazol-5-yl)imidazol-2-yl]-2- fluorobenzonitrile 100
4-[5-Chloro-4-[(3S)-3-(dimethylamino)pyrrolidine-1- B
carbonyl]-1-(2-methylindazol-5-yl)imidazol-2-yl]-2-
fluorobenzonitrile 101
4-[5-Chloro-1-(3-chloro-2-methylindazol-5-yl)-4-[(3S)- A
3-(dimethylamino)pyrrolidine-1-carbonyl]imidazol-2-
yl]-2-fluorobenzonitrile 102
4-[4-[(3S)-3-(Dimethylamino)pyrrolidine-1-carbonyl]- A
1-(2,3-dimethylindazol-5-yl)-5-methylimidazol-2-yl]-2-
fluorobenzonitrile 103
4-[1-(2,3-Dimethylindazol-5-yl)-5-methyl-4-[(3S)-3- A
(methylamino)pyrrolidine-1-carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 104
2-(4-Cyano-3-fluorophenyl)-1-(2,3-dimethylindazol-5- A
yl)-5-methyl-N-[(3R)-piperidin-3-yl]imidazole-4- carboxamide 105
4-[1-(2,3-Dimethylindazol-5-yl)-5-methyl-4-[(3R)-3- A
(methylamino)piperidine-1-carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 110
4-[1-(3-Chloro-6-fluoro-2-methylindazol-5-yl)-4-[(3S)- A
3-(dimethylamino)pyrrolidine-1-carbonyl]-5-
methylimidazol-2-yl]-2-fluorobenzonitrile 111
4-[1-(3-Chloro-6-fluoro-2-methylindazol-5-yl)-5- A
methyl-4-[(3S)-3-(methylamino)pyrrolidine-1-
carbonyl]imidazol-2-yl]-2-fluorobenzonitrile 112
4-[1-(3-Chloro-6-fluoro-2-methylindazol-5-yl)-4-[(3S)- A
3-(dimethylamino)pyrrolidine-1-carbonyl]-5-
methylimidazol-2-yl]-2-fluorobenzonitrile 113
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-[(3S)-3- A
(methylamino)pyrrolidine-1-carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 114
1-(3-Chloro-2-methylindazol-5-yl)-2-(4-cyano-3- A
fluorophenyl)-N-[(3R)-piperidin-3-yl]imidazole-4- carboxamide 115
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-[(3R)-3- A
(methylamino)piperidine-1-carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 116
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-[(3S)-3- A
(methylamino)piperidine-1-carbonyl]imidazol-2-yl]-2-
fluorobenzonitrile 117
1-(3-Chloro-2-methylindazol-5-yl)-2-(4-cyano-3- A
fluorophenyl)-5-methyl-N-[(3R)-piperidin-3-
yl]imidazole-4-carboxamide 118
4-[1-(3-Chloro-2-methylindazol-5-yl)-5-methyl-4- A
[(3S)-3-(methylamino)piperidine-1-carbonyl]imidazol-
2-yl]-2-fluorobenzonitrile Note: Assay IC.sub.50 data are
designated within the following ranges: A: .ltoreq.0.10 .mu.M B:
>0.10 .mu.M to .ltoreq.1.0 .mu.M C: >1.0 .mu.M to .ltoreq.10
.mu.M D: >10 .mu.M
Example 4: Kasumi-1 AML Cell Line Proliferation Assay (Cell-MTS
Assay)
Colorimetric cellular assay to assess the ability of LSD-1 small
molecule inhibitors to effect the proliferation of the established
AML cancer cell line Kasumi-1.
Assay Background
The LSD-1 protein has been shown to play a key role in the biology
of a variety of cancer types including SCLC and AML. To demonstrate
small molecule inhibition of LSD-1 as a potential anti-cancer
therapy, an assay to measure the degree of proliferative inhibition
in an established cancer cell line of AML was implemented.
Assay Principle
This Cell-MTS assay is a 7-day plate based colorimetric assay which
quantifies the amount of newly generated NADH in the presence and
absence of test compound. These NADH levels are used as a proxy for
the quantification of cancer cell proliferation.
Assay Method in Brief
The established cancer cell line Kasumi-1 with a verified p53
mutation were purchased from American Type Culture Collection
(ATCC) and routinely passaged according to ATCC published
protocols. For routine assay these cells were seeded at a density
of 20,000 cells per 96-well. 24 hours after plating, cells received
an 11 point dilution of test compound with final concentration
ranges from 100 .mu.M to 2.0 nM. Cells are incubated in the
presence of compound for 168 hours at 37.degree. C., 5% CO.sub.2.
At the end of this compound incubation period, 80 .mu.l of media is
removed and 20 .mu.L of CellTiter 96.RTM. AQueous Non-Radioactive
Cell Proliferation Assay solution (Promega) is added. The cells are
incubated until the OD490 is >0.6. IC.sub.50 values are
calculated using the IDBS XLfit software package and include
background subtracted OD490 values and normalization to DMSO
controls.
Table 5 provides the Kasumi-1 cellular IC.sub.50 values of various
substituted heterocyclic compounds disclosed herein.
TABLE-US-00005 TABLE 5 Chemical Kasumi-1 Synthesis IC.sub.50
Example Name (.mu.M) 12
4-[4-[(3R)-3-aminopiperidine-1-carbonyl]-1-(4- A
methoxyphenyl)-5-methylimidazol-2-yl]-2- fluorobenzonitrile 14
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-1-(4- A
methoxyphenyl)-5-methylimidazol-2-yl]-2- fluorobenzonitrile 16
4-[4-[(3R)-3-aminopiperidine-1-carbonyl]-1-(3- A
fluoro-4-methoxyphenyl)-5-methylimidazol-2-yl]-
2-fluorobenzonitrile 18
4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]-1-(3- A
fluoro-4-methoxyphenyl)-5-methylimidazol-2-yl]-
2-fluorobenzonitrile 64 2-Fluoro-4-[1-(3-fluoro-4-methoxyphenyl)-5-
A methyl-4-[(3S)-3-(methylamino)pyrrolidine-1-
carbonyl]imidazol-2-yl]benzonitrile 67
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5- A
fluoro-1-(3-fluoro-4-methoxyphenyl)imidazol-2-
yl]-2-fluorobenzonitrile 70
2-Fluoro-4-[1-(4-methoxyphenyl)-5-methyl-4- A
[(3R)-3-(methylamino)piperidine-1-
carbonyl]imidazol-2-yl]benzonitrile 76
4-[4-[(3R)-3-Aminopiperidine-1-carbonyl]-5- A
chloro-1-(3-chloro-2-methylindazol-5-
yl)imidazol-2-yl]-2-fluorobenzonitrile 88
4-[4-[3-(Aminomethyl)azetidine-1-carbonyl]-1-(3- A
fluoro-4-methoxyphenyl)-5-methylimidazol-2-yl]-
2-fluorobenzonitrile 94 4-[4-[(3S)-3-(Dimethylamino)pyrrolidine-1-
A carbonyl]-5-methyl-1-(2-methylindazol-5-
yl)imidazol-2-yl]-2-fluorobenzonitrile 96
4-[1-(3-Chloro-2-methylindazol-5-yl)-4-[(3S)-3- A
(dimethylamino)pyrrolidine-1-carbonyl]-5-
methylimidazol-2-yl]-2-fluorobenzonitrile Note: Assay IC.sub.50
data are designated within the following ranges: A: .ltoreq.0.10
.mu.M B: >0.10 .mu.M to .ltoreq.1.0 .mu.M C: >1.0 .mu.M to
.ltoreq.10 .mu.M D: >10 .mu.M
Example 5: In Vivo Xenograph Study--MCF-7 Xenograph
Time release pellets containing 0.72 mg 17-13 Estradiol are
subcutaneously implanted into nu/nu mice. MCF-7 cells are grown in
RPMI containing 10% FBS at 5% CO.sub.2, 37.degree. C. Cells are
spun down and re-suspended in 50% RPMI (serum free) and 50%
Matrigel at 1.times.10.sup.7 cells/mL. MCF-7 cells are
subcutaneously injected (100 .mu.L/animal) on the right flank 2-3
days post pellet implantation and tumor volume
(length.times.width.sup.2/2) is monitored bi-weekly. When tumors
reach an average volume of .about.200 mm.sup.3 animals are
randomized and treatment is started. Animals are treated with
vehicle or compound daily for 4 weeks. Tumor volume and body weight
are monitored bi-weekly throughout the study. At the conclusion of
the treatment period, plasma and tumor samples are taken for
pharmacokinetic and pharmacodynamic analyses, respectively.
Example 6: In Vivo Xenograph Study--LNCaP Xenograph
LNCaP cells with a stable knockdown of LSD1 (shLSD1 cells) or
control cells (such as shNTC cells) are inoculated in the dorsal
flank of nude mice by subcutaneous injection (such as
3.times.10.sup.6 cells in 100 .mu.l of 50% RPMI 1640/BD Matrigel).
Mouse weight and tumor size are measured once per week and tumor
volume is estimated using the formula (7i/6)(L.times.W), where
L=length of tumor and W=width of tumor. A two sample t-test is
performed to determine statistical differences in mean tumor volume
between the two groups.
Unmodified LNCaP cells are inoculated by subcutaneous injection
into the dorsal flank of nude mice (such as 3.times.10.sup.6 cells
in 100 .mu.l of 50% RPMI 1640/BD Matrigel). After three weeks, mice
are injected intraperitoneally once per day with water (control),
pargyline (0.53 mg or 1.59 mg; 1 or 3 mM final concentration,
assuming 70% bioavailability), or XB154 (4 or 20 .mu.g; 1 or 5
.mu.M final concentration, assuming 70% bioavailability) or treated
with a test compound (5 mg/kg each week or 10 mg/kg each week).
Treatment continues for three weeks, during which time mouse weight
and tumor volume are measured as above.
shLSDI LNCaP cells or control cells are injected in nude mice as
above. After three weeks, mice are treated with 2.6 .mu.g mitomycin
C (predicted final concentration of 1 .mu.M assuming 40%
bioavailability), olaparib (for example, about 0.5 mg/kg to 25
mg/kg), or vehicle intraperitoneally once per day for three weeks.
In other examples, unmodified LNCaP cells are injected in nude mice
as above.
After three weeks, mice are treated with test compounds, or vehicle
as above, plus MMC or olaparib. Treatment continues for three
weeks, during which time mouse weight and tumor volume are measured
as above.
A decrease in tumor volume compared to control in mice injected
with shLSD1 cells indicates that LSD1 inhibition decreases tumor
growth in vivo.
Similarly, a decrease in tumor volume compared to control in mice
injected with LNCaP cells and treated with a compound disclosed
herein indicates that LSD1 inhibition decreases tumor growth in
vivo. Finally, a decrease in tumor volume in mice injected with
LNCaP cells and treated with a compound disclosed herein plus
olaparib as compared to mice treated with a compound disclosed
herein alone indicates that inhibition of LSD1 plus inhibition of
PARP decreases tumor growth in vivo.
The harvested xenograft tissue is examined for evidence of LSD1
inhibition. This is assessed with Western blots to examine global
levels of the 2MK4 and 2MK9 histone marks, expression of FA/BRCA
genes, FANCD2 ubiquitination, and LSD1 protein levels in the cases
of the shRNA cells. A decrease in one or more of these parameters
indicates the effective inhibition of LSD 1. Additionally, effects
on DNA damage repair are assessed with staining for H2AX foci.
III. Preparation of Pharmaceutical Dosage Forms
Example 1: Oral Tablet
A tablet is prepared by mixing 48% by weight of a compound of
Formula (I), or a pharmaceutically acceptable salt thereof, 45% by
weight of microcrystalline cellulose, 5% by weight of
low-substituted hydroxypropyl cellulose, and 2% by weight of
magnesium stearate. Tablets are prepared by direct compression. The
total weight of the compressed tablets is maintained at 250-500
mg.
* * * * *